MXPA03008143A - Heterocyclic compounds. - Google Patents
Heterocyclic compounds.Info
- Publication number
- MXPA03008143A MXPA03008143A MXPA03008143A MXPA03008143A MXPA03008143A MX PA03008143 A MXPA03008143 A MX PA03008143A MX PA03008143 A MXPA03008143 A MX PA03008143A MX PA03008143 A MXPA03008143 A MX PA03008143A MX PA03008143 A MXPA03008143 A MX PA03008143A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- piperazin
- indol
- methanone
- alkyl
- Prior art date
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 3
- -1 nitro, amino Chemical group 0.000 claims description 280
- 150000001875 compounds Chemical class 0.000 claims description 209
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 54
- 229910052801 chlorine Inorganic materials 0.000 claims description 51
- 229910052731 fluorine Inorganic materials 0.000 claims description 46
- 238000011282 treatment Methods 0.000 claims description 45
- 229910052794 bromium Inorganic materials 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 150000002148 esters Chemical class 0.000 claims description 31
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 206010061218 Inflammation Diseases 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 230000004054 inflammatory process Effects 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 16
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- 230000001404 mediated effect Effects 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000002947 alkylene group Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 125000004450 alkenylene group Chemical group 0.000 claims description 7
- 208000010668 atopic eczema Diseases 0.000 claims description 7
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 7
- KPSNDDMXZUDTOT-UHFFFAOYSA-N (5,7-dichloro-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(Cl)=CC(Cl)=C2N1 KPSNDDMXZUDTOT-UHFFFAOYSA-N 0.000 claims description 6
- UNZKXQGDHWYPDV-UHFFFAOYSA-N (5-bromo-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(Br)=CC=C2N1 UNZKXQGDHWYPDV-UHFFFAOYSA-N 0.000 claims description 6
- HUQJRYMLJBBEDO-UHFFFAOYSA-N (5-chloro-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical group C1CN(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 HUQJRYMLJBBEDO-UHFFFAOYSA-N 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 230000000172 allergic effect Effects 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- RRZGZMUPDJEOKD-UHFFFAOYSA-N (5,7-difluoro-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(F)=CC(F)=C2N1 RRZGZMUPDJEOKD-UHFFFAOYSA-N 0.000 claims description 5
- XJMMCJLQDZQDAQ-UHFFFAOYSA-N (5-methyl-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(C)=CC=C2N1 XJMMCJLQDZQDAQ-UHFFFAOYSA-N 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- NRHQFEPCASYTRU-UHFFFAOYSA-N (3,5-dichloro-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=C(Cl)C2=CC(Cl)=CC=C2N1 NRHQFEPCASYTRU-UHFFFAOYSA-N 0.000 claims description 4
- MIGREITXIMIAAD-UHFFFAOYSA-N (5-fluoro-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(F)=CC=C2N1 MIGREITXIMIAAD-UHFFFAOYSA-N 0.000 claims description 4
- IFQWJQPPUGREON-UHFFFAOYSA-N (6-chloro-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical group C1CN(C)CCN1C(=O)C1=CC2=CC=C(Cl)C=C2N1 IFQWJQPPUGREON-UHFFFAOYSA-N 0.000 claims description 4
- DJLVUHAOULMUID-UHFFFAOYSA-N (7-chloro-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC=CC(Cl)=C2N1 DJLVUHAOULMUID-UHFFFAOYSA-N 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- UBFYJOYAUHCGIB-UHFFFAOYSA-N 1h-indol-2-yl-(4-methylpiperazin-1-yl)methanethione Chemical compound C1CN(C)CCN1C(=S)C1=CC2=CC=CC=C2N1 UBFYJOYAUHCGIB-UHFFFAOYSA-N 0.000 claims description 3
- 101100439662 Arabidopsis thaliana CHR5 gene Proteins 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 208000029462 Immunodeficiency disease Diseases 0.000 claims description 3
- 208000018501 Lymphatic disease Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 230000006022 acute inflammation Effects 0.000 claims description 3
- 208000038016 acute inflammation Diseases 0.000 claims description 3
- 230000009285 allergic inflammation Effects 0.000 claims description 3
- 208000037976 chronic inflammation Diseases 0.000 claims description 3
- 230000006020 chronic inflammation Effects 0.000 claims description 3
- 208000018555 lymphatic system disease Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- XSAHKLVDRXTVCY-UHFFFAOYSA-N (4-bromo-7-methyl-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=C(Br)C=CC(C)=C2N1 XSAHKLVDRXTVCY-UHFFFAOYSA-N 0.000 claims description 2
- RJTNRVNBDUTWPV-UHFFFAOYSA-N (4-methylpiperazin-1-yl)-[5-(trifluoromethyl)-1h-indol-2-yl]methanone Chemical group C1CN(C)CCN1C(=O)C1=CC2=CC(C(F)(F)F)=CC=C2N1 RJTNRVNBDUTWPV-UHFFFAOYSA-N 0.000 claims description 2
- KRMDQEGOJQMNFM-UHFFFAOYSA-N (5,6-difluoro-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(F)=C(F)C=C2N1 KRMDQEGOJQMNFM-UHFFFAOYSA-N 0.000 claims description 2
- OIDBUWGGJGLDDO-UHFFFAOYSA-N (5,7-difluoro-1h-indol-2-yl)-(3-methylpiperazin-1-yl)methanone Chemical compound C1CNC(C)CN1C(=O)C1=CC2=CC(F)=CC(F)=C2N1 OIDBUWGGJGLDDO-UHFFFAOYSA-N 0.000 claims description 2
- KLVJLQVELOBAER-UHFFFAOYSA-N (5-amino-7-bromo-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(N)=CC(Br)=C2N1 KLVJLQVELOBAER-UHFFFAOYSA-N 0.000 claims description 2
- AQUSNLWYFYWCMW-UHFFFAOYSA-N (5-amino-7-methyl-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(N)=CC(C)=C2N1 AQUSNLWYFYWCMW-UHFFFAOYSA-N 0.000 claims description 2
- JIDUEEHXLAWFDN-UHFFFAOYSA-N (5-chloro-1h-indol-2-yl)-[3-(hydroxymethyl)-4-methylpiperazin-1-yl]methanone Chemical compound C1C(CO)N(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 JIDUEEHXLAWFDN-UHFFFAOYSA-N 0.000 claims description 2
- NPUXEJRHDICFIK-UHFFFAOYSA-N (5-chloro-1h-indol-2-yl)-[3-(methoxymethyl)-4-methylpiperazin-1-yl]methanone Chemical compound C1CN(C)C(COC)CN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 NPUXEJRHDICFIK-UHFFFAOYSA-N 0.000 claims description 2
- PBRFMCGYUNROHC-UHFFFAOYSA-N (5-chloro-1h-indol-2-yl)-[3-[(dimethylamino)methyl]-4-methylpiperazin-1-yl]methanone Chemical compound C1CN(C)C(CN(C)C)CN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 PBRFMCGYUNROHC-UHFFFAOYSA-N 0.000 claims description 2
- JZVAFAROGGVKSR-UHFFFAOYSA-N (5-chloro-1h-indol-2-yl)-[4-methyl-2-(methylaminomethyl)piperazin-1-yl]methanone Chemical compound CNCC1CN(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 JZVAFAROGGVKSR-UHFFFAOYSA-N 0.000 claims description 2
- UVLQFDWCBMFYFI-UHFFFAOYSA-N (6-bromo-5-hydroxy-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(O)=C(Br)C=C2N1 UVLQFDWCBMFYFI-UHFFFAOYSA-N 0.000 claims description 2
- DUJPTGAJPDKGAQ-UHFFFAOYSA-N (7-amino-5-bromo-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(Br)=CC(N)=C2N1 DUJPTGAJPDKGAQ-UHFFFAOYSA-N 0.000 claims description 2
- WXERHPPXWANRNP-UHFFFAOYSA-N (7-amino-5-methyl-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(C)=CC(N)=C2N1 WXERHPPXWANRNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 2
- GSYVRMRACDKTBV-UHFFFAOYSA-N 1-(5-chloro-1h-indole-2-carbonyl)-n,4-dimethylpiperazine-2-carboxamide Chemical compound CNC(=O)C1CN(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 GSYVRMRACDKTBV-UHFFFAOYSA-N 0.000 claims description 2
- GKIVJCJLOYQIJI-UHFFFAOYSA-N 1-(5-chloro-1h-indole-2-carbonyl)-n,n,4-trimethylpiperazine-2-carboxamide Chemical compound CN(C)C(=O)C1CN(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 GKIVJCJLOYQIJI-UHFFFAOYSA-N 0.000 claims description 2
- IZFVCJFCMZZVFH-UHFFFAOYSA-N 4-(5-chloro-1h-indole-2-carbonyl)-1-methylpiperazine-2-carboxamide Chemical compound C1C(C(N)=O)N(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 IZFVCJFCMZZVFH-UHFFFAOYSA-N 0.000 claims description 2
- OAXAKNYWVPFJLG-UHFFFAOYSA-N 4-(5-chloro-1h-indole-2-carbonyl)-n,1-dimethylpiperazine-2-carboxamide Chemical compound C1CN(C)C(C(=O)NC)CN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 OAXAKNYWVPFJLG-UHFFFAOYSA-N 0.000 claims description 2
- DDCUZKOPUCCDCO-UHFFFAOYSA-N 4-(5-chloro-1h-indole-2-carbonyl)-n,n,1-trimethylpiperazine-2-carboxamide Chemical compound C1CN(C)C(C(=O)N(C)C)CN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 DDCUZKOPUCCDCO-UHFFFAOYSA-N 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- YMOVPLMHEDUBQD-UHFFFAOYSA-N methyl 4-(5-chloro-1h-indole-2-carbonyl)-1-methylpiperazine-2-carboxylate Chemical compound C1CN(C)C(C(=O)OC)CN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 YMOVPLMHEDUBQD-UHFFFAOYSA-N 0.000 claims description 2
- 229910021481 rutherfordium Inorganic materials 0.000 claims description 2
- FHWGDTRVUPZNRN-UHFFFAOYSA-N (5-bromo-1-benzofuran-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC(Br)=CC=C2O1 FHWGDTRVUPZNRN-UHFFFAOYSA-N 0.000 claims 3
- JHFKQCKHXVCFDJ-UHFFFAOYSA-N (7-bromo-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC=CC(Br)=C2N1 JHFKQCKHXVCFDJ-UHFFFAOYSA-N 0.000 claims 3
- HNVQQKFVQDIMFD-UHFFFAOYSA-N 1h-indol-2-yl-(3-methylpiperazin-1-yl)methanone Chemical compound C1CNC(C)CN1C(=O)C1=CC2=CC=CC=C2N1 HNVQQKFVQDIMFD-UHFFFAOYSA-N 0.000 claims 3
- PKZYVJJVJRXPJA-UHFFFAOYSA-N (5,7-difluoro-1h-indol-2-yl)-piperazin-1-ylmethanone Chemical compound C=1C2=CC(F)=CC(F)=C2NC=1C(=O)N1CCNCC1 PKZYVJJVJRXPJA-UHFFFAOYSA-N 0.000 claims 1
- DHZGCZWLZMNMLB-UHFFFAOYSA-N (5-chloro-1h-indol-2-yl)-[2-[(dimethylamino)methyl]-4-methylpiperazin-1-yl]methanone Chemical compound CN(C)CC1CN(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 DHZGCZWLZMNMLB-UHFFFAOYSA-N 0.000 claims 1
- ACDZTPPWMOERQW-UHFFFAOYSA-N (5-chloro-1h-indol-2-yl)-[4-methyl-3-(methylaminomethyl)piperazin-1-yl]methanone Chemical compound C1CN(C)C(CNC)CN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 ACDZTPPWMOERQW-UHFFFAOYSA-N 0.000 claims 1
- DSNKBSVDYCXHGT-UHFFFAOYSA-N (6-bromo-7-methyl-1h-indol-2-yl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC2=CC=C(Br)C(C)=C2N1 DSNKBSVDYCXHGT-UHFFFAOYSA-N 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- NZGUHJOFWIGKRC-UHFFFAOYSA-N 1-(5-chloro-1h-indole-2-carbonyl)-4-methylpiperazine-2-carboxamide Chemical compound NC(=O)C1CN(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 NZGUHJOFWIGKRC-UHFFFAOYSA-N 0.000 claims 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
- KVQFETHEKZUWFV-UHFFFAOYSA-N methyl 1-(5-chloro-1h-indole-2-carbonyl)-4-methylpiperazine-2-carboxylate Chemical group COC(=O)C1CN(C)CCN1C(=O)C1=CC2=CC(Cl)=CC=C2N1 KVQFETHEKZUWFV-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 215
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 35
- 239000002904 solvent Substances 0.000 description 35
- 238000004587 chromatography analysis Methods 0.000 description 34
- 239000000741 silica gel Substances 0.000 description 34
- 229910002027 silica gel Inorganic materials 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- 229910052938 sodium sulfate Inorganic materials 0.000 description 29
- 235000011152 sodium sulphate Nutrition 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 26
- 239000012267 brine Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 241000699670 Mus sp. Species 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 229940125904 compound 1 Drugs 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 229910021529 ammonia Inorganic materials 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 125000004122 cyclic group Chemical group 0.000 description 13
- 210000000224 granular leucocyte Anatomy 0.000 description 13
- 239000000284 extract Substances 0.000 description 12
- 239000003396 histamine H4 receptor antagonist Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- 229940119240 Histamine H4 receptor antagonist Drugs 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 229920000392 Zymosan Polymers 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229960005076 sodium hypochlorite Drugs 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
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- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
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Abstract
Heterocyclic compounds and methods of making them and using them.
Description
COMPOUNDS HETEROC1CL1COS
FIELD OF THE INVENTION
The invention relates to novel, pharmaceutically active, fused heterocyclic compounds and to methods for using them to treat or prevent disorders and conditions mediated by histamine H4 receptor.
ANTECENDENTS OF THE INVENTION
Histamine was first identified as a hormone (Barger et al., J. Physiology 41: 19-59, 1910) and has been shown to play an important role in a variety of physiological processes, including the inflammatory "triple response" by receptors. from (Ash et al., Br. J. Pharmacology 27: 427-439, 1966), secretion of gastric acids by H2 receptors (Black et al., Nature 236: 385-390, 1972), and neurotransmitter release in the central nervous system through H2 receptors (Arrang et al., Nature 302: 832-837, 1983) (for review see Hill et al., Pharmacol Rev. 49: 253-278, 1997). It has been shown that all three histamine receptor subtypes belong to the superfamily of G-protein coupled receptors (Gantz et al., Proc. Nati, Acad. Sci. USA 88: 429-433, 1991; Lovenberg et al., Mol.Pharmacol., 55: 1 101-1 107, 1999; Yamashita et al., Proc. Nati, Acad. Sci. USA 88: 1 1515-1 1519, 1991). However, there are additional functions of histamine that have been reported, for which a receiver has not been identified. For example, in 1994, Raible et al. demonstrated that histamine and R-a-methylhistamine could activate calcium mobilization in human eosinophils (Raible et al., Am. J. Resp. Crit. Care Mec. 149: 1506-1511, 1994). These responses were blocked by the H3 receptor antagonist thioperamide. However, R-α-methylhistamine was significantly less potent than histamine which was not consistent with the involvement of known H3 receptor subtypes. Therefore, Raible et al. postulated the hypothesis of the existence of a novel histamine receptor on eosinophils that was non-H-i, -H2, or -H3. Very recently several groups (Oda et al., J. Biol. Chem. 275 (47): 36781-36786, 2000; Liu et al., Mol. Pharmacol. 59: 420-426, 2001; Nguyen et al., Mol. Pharmacol 59: 427-433, 2001; Zhu et al., Mol Pharmacol 59 (3): 434-441, 2001; Morse et al., J. Pharmacol. Exp. Ther 296 (3): 1058 -1066, 2001) have identified and characterized a fourth subtype of histamine receptor, the H4 receptor. This receptor is a seven-transmembrane G-protein coupled receptor, 390 amino acids, with approximately 40% homology to the histamine H3 receptor. Unlike the H3 receptor, which is located mainly in the brain, the H4 receptor is expressed at higher levels in neutrophils and mast cells, among other cells, as reported by Morse et al. (see above). The events that induce the inflammatory response include physical stimulation (including trauma), chemical stimulation, infection and invasion by a foreign body. The inflammatory response is characterized by pain, increased temperature, redness, swelling, reduced function or a combination of these. Many conditions, such as allergies, asthma, chronic obstructed pulmonary disease (COPD), atherosclerosis and autoimmune diseases, including rheumatoid arthritis and lupus, are characterized by excessive or prolonged inflation. The inhibition of leukocyte recruitment can provide significant therapeutic value. Inflammatory diseases or diseases or conditions mediated by inflammation include, but are not limited to, acute inflammation, allergic inflammation and chronic inflammation. The degranulation of mast cells (exocytosis) leads to an inflammatory response that can initially be characterized by a reaction of hives and inflammation. A wide variety of immunological stimuli (eg, allergens or antibodies) and non-immunological (eg, chemical) stimuli can cause the activation, recruitment and degranulation of mast cells. Activation of mast cells initiates allergic inflammatory responses (H), which in turn cause the recruitment of other effector cells that also contribute to the inflammatory response. Histamine H2 receptors modulate gastric acid secretion, and histamine H3 receptors affect the release of neurotransmitter in the central nervous system. Examples of textbooks on the subject of inflammation include J. I. Gallin and R. Snyderman, Inflammation: Basic Principles and Clinical Correlates, 3rd edition, (Lippincott Williams &; Wiikins, Philadephia, 1999); V. Stvrtinova, J. Jakubovsky and I. Hulin. "Inflammation and Fever". Pathophysiology Principles of Diseases (Textbook for Medical Students, Academic Press, 1995): Cecil et al., Textbook of Medicine, 18th edition (W. B. Saunders Company, 1988); and Steadmans Medical Dictionary. A brief description of the present invention is given below.
BRIEF DESCRIPTION OF THE INVENTION
The invention relates to a compound of the formula (I):
where Ri is Ra, RaRtr. Ra-0-Rb or (Rc) (Rd) N-Rb-, where Ra is H, cyano, - (C = O) N (R0) (Rd), -C (= NH) (NH2), alkyl Ci_101 C3-8 alkenyl, C3-B cycloalkenyl, C2-5 heterocyclic radical, or phenyl; wherein R is alkylene of Ci-8, alkenylene of C2-8, cycloalkylene of C3-8, heterocyclic radical of C3-8 bivalent, or phenylene; and R c and ¾ are each independently H, Ci-8 alkyl, C 2-8 alkenyl. C3-8 cycloalkyl or phenyl; R2 is H, methyl, ethyl, NRpRq, - (CO) NRpRq, - (CO) ORr, -CH2NRpRq, or CH2OR; wherein R p, R q, and R r are independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl; (C3-cycloalkyl) (C1-2 alkylene), benzyl or phenethyl; or Rp and Rq taken together with the nitrogen to which they are attached, form a 4- to 7-membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N; R3 is H, methyl, ethyl, NRsRt, - (CO) NRsRt) - (CO) ORU) -CH2NRsRt, or CH2ORu; wherein Rs, Rt, and Ru are independently selected from Ci-6 alkyl, C3-6 cycloalkyl, phenyl; (C3-6 cycloalkyl) (d-2-alkylene), benzyl or phenethyl; or Rs and Rt taken together with the nitrogen to which they are attached, form a 4- to 7-membered heterocyclic ring with 0 or 1 heteroatoms selected from O, S, and N; R5- is methyl, ethyl or H; R6 'is methyl, ethyl or H, R7- is methyl, ethyl or H, XI is CR3; R3 is F, Cl, Br, CHO, Rf, RfRg-, RrO-Rg-, or (Rh) (R1) N-Rg-, wherein Rf is H, Ci-6 alkyl, C2-6 alkenyl , C2-5 heterocyclic radical or phenyl; wherein Rg is Ci-6 alkylene, C2-6 alkenylene. C3-6 cycloalkylene, divalent C3-6 heterocyclic radical or phenylene; and Rh and Rj are each independently H, C1.6 alkyl, C2-6 alkenyl, C3.6 cycloalkyl or phenyl; X2 is NRe or O, provided that X2 is NRe where X1 is N; Re is H or C-i-6 alkyl; X3 is N; Z is = O or = S; each of R 4 and R 6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C-i-4 alkoxy or C-M alkyl; R5 is H, F, Cl, BR, I, (C = 0) Rj, OH, nitro, NRjRk, cyano, phenyl, -OCH2-Ph C1-4 alkoxy or C-u alkyl; R7 is H, F, Cl, Br, I, (C = 0) Rm, OH, nitro, NR, Rm, cyano, phenyl, -OCH2-Ph Ci_4 alkoxy or Ci_4 alkyl; wherein each of Rj, Rk, Ri, and Rm is independently selected from H, C-i-6alkyl, hydroxy, phenyl, benzyl, phenethyl, and C-i-6alkoxy; each of the above hydrocarbyl groups (including alkyl, alkoxy, phenyl, benzyl, cycloalkyl, etc.) or heterocyclics being independently and optionally substituted with 1 to 3 substituents selected from C 1-3 alkyl, halogen, hydroxy, amino and alkoxy from d-3; wherein n is 0, 1 or 2; where n is 2, the portion - (CHR5 ') n = 2-is - (CHR5-CHR7"), where CHR5' is between CHR6- and CHR7-, provided that at least one of Ri, R2, R3 , 4, Rs, 6 and 7 is different from H when Z is O, and provided that, where Z is O, n = 1, and each of R4, R5, R6, R2 \ Ry, Rff and! ¾| is H, (or at least 7, 8 or 9 of these 10 limitations apply) then (a) where X2 is NH, then R-? is (i) not methyl, pyridyl, phenyl or benzyl, or (ii) ) is selected from the described possibilities, but not Ci-2 alkyl and not a six-membered aryl or heteroaryl containing six-membered nitrogen, or phenyl (Ci-2 alkylene) (alternatively, whenever Z is O, n) = 1, and X2 is NH, then at least two (or three) of R, R5, e, R7, R2-, 3 ', R5' and e- is different from H), and (b) where X2 is O, then R1 is not methyl, and provided that, where Z is O, X2 is NH, n = 1, R1 is methyl, each of R4, R6, R7, R ?, R ^ Rs-, and R6 - is H (or at least 7, 8, 9 or 10 of these 1 1 limitations apply) can), then R5 is (i) non-methoxy, (ii) non-methoxy, or ethoxy, (ii) non-C1-4 alkoxy, or (iv) non-methoxy or hydroxy; pharmaceutically acceptable salt, ester or amide thereof. In accordance with an aspect of the invention, the invention relates to compounds of the following formula (Ib):
(Ib) wherein Ri is Ra, RaRb-, Ra-0-R-, or (Rc) (Rd) N-Rb-, where Ra is H, C1-10 alkyl, C3-8 alkenyl, cycloalkyl of C3-8, C2-5 heterocyclic radical or phenyl; wherein R is Ci-8 alkylene, C3-8 alkenylene, C3-8 cycloalkylene, divalent C3-8 heterocyclic radical or phenylene; and R c and a are each independently H, C-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl, or phenyl; R2 is ortho (as R2- in formula (I)) or meta (as R3> in formula (I)), and is methyl or H; Xi is CR3; R3 is F, Cl, Br, Rf, RfRg-, Rf-0-Rg, or (Rh) (R1) N-Rg-, wherein Rf is H, Ci-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C2-5 heterocyclic radical or phenyl; wherein Rg is C 1-6 alkylene, C 3-6 cycloalkylene alkenylene, C 6-6 bivalent heterocycle or phenylene radical; and Rh and R, are each independently H, C6 alkyl, C2-6 alkenyl, C3_6 cycloalkyl, or phenyl; X2 is NRe or O, provided that X2 is NRe when X1 is N; Re is H or Ci-6 alkyl; X3 is N; Z is = 0 or = S; each of R4 and R6 is independently H, F, CI, Br, I,
COOH, OH, nitro, amino, cyano, C1-4 alkoxy or Ci-4 alkyl; R5 is H, F, Cl, Br, I, (C = 0) Rj, OH, nitro, NRjRk, cyano, -OCH2-Ph, C-i-4 alkoxy or C-i-4 alkyl; R7 is H, F, Cl, Br, I, (C = 0) Rm, OH, nitro, NRjRm, cyano, Ci-4 alkoxy, or C1-4 alkyl; wherein each of Rj, Rk, Ri, Rm, is independently selected from H, Ci-6 alkyl, hydroxy and Ci-6 alkoxy, and each of the hydrocarbyl or heterocyclic groups being independently and optionally substituted with 1 and 3 substituents selected from Ci-3 alkyl, halogen, hydroxy, amino and Ci-3 alkoxy; provided that at least one of R-i, R2, R3, R4, R5, 6 and 7 is different from H when Z is = 0; or a pharmaceutically acceptable salt, ester or amide thereof. The invention also relates to methods for making and using those compounds in a pharmaceutical composition, packaged drugs and in the treatment of diseases and conditions mediated by H4, particularly those where it is convenient to antagonize the H4 receptor. For example, expression of the H4 receptor in immune cells, including some leukocytes and mast cells, establishes it as an important target for therapeutic intervention in a range of immunological and inflammatory disorders (such as allergic, chronic or acute inflammation). Specifically, it is expected that the H 4 receptor ligands are useful for the treatment or prevention of various disease states in mammals. Examples include: inflammatory disorders (such as those mediated by leukocytes or mast cells), asthma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, autoimmune disease, lymphatic disorders, atherosclerosis and disorders of immunodeficiency. In addition, the H4 receptor ligands may be useful as adjuvants for chemotherapy. In the above methods of the treatment, the invention also includes the use of compounds described in formulas (I) and (Ib) without the conditions such as "provided that at least one of Ri, l¾, F¾. R4, R5, R6 , and R7 is other than H when Z is O "above in pharmaceutical compositions for treating conditions mediated by H4 and in methods of treating diseases mediated by H4. Said compound is, for example, Example 4. Significant synthetic intermediates of the above compounds include those wherein one or more of R4, R5, R6, and R7 is Br, I, cyano, nitro, alkoxy, or -OCH2Ph, which it can also be modified to provide a wide range of substituents. Other features and advantages of the invention will be apparent from the following detailed description, examples and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to compounds of the formulas (I) and (Ib), to methods for making them, and to methods for using them in the preparation of pharmaceutical compositions for the treatment or prevention of diseases or conditions mediated by H4.
A. Terms' The following terms are defined below and by their use throughout the description. "Alkyl" includes straight and branched chain hydrocarbons optionally substituted with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, etc. Alkyl does not include cycloalkyl. "Alkenyl" includes straight and branched chain hydrocarbon radicals as mentioned above with at least one carbon-carbon double bond (sp2). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyl, pentenyl, hexa -2,4-dienyl, etc. The hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyl in the present invention. Alkenyl does not include cycloalkenyl. "Alkynyl" includes straight and branched chain hydrocarbon radicals as mentioned above with at least one carbon-carbon triple bond (sp). Alkynyl include ethynyl, propynyl, butynyl, and pentinyl. The hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyl in the present. The alkynyl does not include cycloalkynyl. "Alkoxy" includes a straight or branched chain alkyl group with a terminal oxygen linking the alkyl group with the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, etc. "Aminoalkyl", "thioalkyl" and "sulfonylalkyl" are analogous to alkoxy, replacing the terminal oxygen atom of the alkoxy with NH (or NR), S, and S02. "Aryl" includes phenyl, naphthyl, biphenylyl, etc., "Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. "Cycloalkenyl" includes cyclobutenyl, cyclobutadienyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclohexatrienyl ( phenyl), cycloheptenyl, etc. "Cycloalkynyl" includes analogous rings with one or more triple bonds. "Heterocyclic radicals" include aromatic and non-aromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom portion (S02, CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence that connects it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a hetero atom such as N -piperidyl or 1-pyrazolyl. Examples of heterocyclic radicals include thiazolyl, furyl, pyranyl, isobenzofuranyl, pyroyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolinyl, furazanyl, pyrrolidinium, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indonilyl and morpholinyl. For example, preferred heterocyclic radicals for Ra include morpholinyl, piperazinyl, pyrrolidinium, pyridyl, cyclohexylimino, cycloheptylimino, and most preferably piperidyl. "Halogen" includes fluorine, chlorine, bromine and iodine, and preferably fluorine or chlorine. "Patient" or "subject" includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) that need observation, experimentation, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient or subject is a human. "Composition" includes a product that comprises the specified ingredients in the specified amounts such as any product that results directly or indirectly from combinations of the specified ingredients in the specified amounts. With respect to the various radicals in the description and in the claims, two general observations are made. The first observation refers to valence. As with all hydrocarbon (hydrocarbyl) radicals, whether saturated, unsaturated or aromatic, and either cyclic or straight-chain or branched, and also the similarity with all heterocyclic radicals, each radical includes substituted radicals of that radical. type and monovalent, divalent and multivalent radicals as indicated in the context of the claims. Hydrocarbyl includes alkoxy, since the alkyl portion of an alkoxy group can be substituted. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (divalent) or more hydrogen atoms removed (multivalent). An example of a bivalent radical joining two parts of the molecule is Rb in formula (I), which can bind N (Rc) (Rd) with the ring nitrogen atom of the remainder of the molecule. Another example of the bivalent portion is an alkylene or alkenylene. Second, radicals or fragments of structure as defined herein are understood to include substituted radicals or structure fragments. By using "alkyl" as an example, "alkyl" is to be understood as including substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3 or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl and 3-iodocyclopentyl), hydroxyalkyl, aminoalkyl, nitroalkyl, alkylalkyl, etc. Preferred substitutions for Ra include methyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoromethoxy, fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl), 1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoroethoxy, fluoro, chloro and bromo and particularly methyl, fluoromethyl, perfluoro , trifluoromethoxy, difluoromethoxy, methoxy and fluoro.
B. Compounds The invention relates to compounds of formulas (I) and (Ib). Preferred compounds include those wherein: (a) X-i is CR3; (b) X3 is N; (c) X2 is N; (d) R1 is H, methyl or ethyl; (e) X2 is N and X † is CR3; (f) X2 is O and X-i is CR3; (g) X2 is N and Z is O; (h) R7 is H or Cl; (i) R1 is methyl or ethyl; (j) f¾-o R2 > is, or both are, H; (k) R3 is H or Cl; (I) each R5 and R7 is independently selected from H, F, Cl and Br; (m) R3 is Cl; (n) at least one of R5 and R7 is F, Cl, Br or methyl; (o) R5, or R7t or both is (are independently selected from) H, F, Cl, or Br; (p) R3 > or R2- is methyl when R1 is H; R3- or R2- is otherwise H; or (q) at least one of R5 and R7 is not H; or (r) combinations thereof. Additional examples of preferred compounds or combinations of the above include those wherein: (s) X3 is N; R3 is H or Cl; R5 is F, Cl, Br, or methyl; and R7 is H, F, Cl, or Br; (t) R3 is H or Cl; R5 is F, Cl, Br or methyl; and R7 is H, F, Cl, Br or methyl; (u) R2 is methyl when R1 is H; R2 is otherwise H; X1 is CR3; R3 is H, F or Cl; X2 is NRe or O, provided that X2 is NRe where X1 is N; Re is H or Ci-3 alkyl; Z is = 0 or = S; each of R 4 and R 6 is independently H, OH, d-4 alkyl, C-w alkoxy, cyano or amino; R5 is H, F, Cl, Br, (C = 0) Rj, OH, amino, cyano, C -4 alkoxy, or C -4 alkyl; R7 is H, F, Cl, Br, (C = 0) Rm, C-4 alkyl, C 1 alkoxy, cyano or amino; and (v) R3- and R2- is methyl or H; is CR3; R3 is H, F or Cl; X2 is NRe or O, provided that X2 is NRe where Xi is N; Re is H or C6 alkyl; Z is = 0 or = S; each of R4 and R6 is H; R5 is H, F, Cl, Br, methyl, ethyl or propyl; and R7 is H, F, Cl, Br or C -4 alkyl. Examples of compounds include: (4-methyl-piperazin-1-yl) - (5-trifluoromethyl-1 H -indol-2-yl) -methanone; (7-amino-5-methyl-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-amino-7-methyl-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (7-amino-5-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-amino-7-bromo-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-fluoro-7-methyl-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (7-fluoro-5-methyl-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (6-bromo-5-hydroxy-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-6-hydroxy-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (6-bromo-7-hydroxy-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (4-bromo-7-hydroxy-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (6-bromo-7-methy1-H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; and (4-bromo-7-methyl-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone. Additional examples of compounds include: (5,7-dichloro-1 H -indol-2-yl) -piperazin-1-yl-methanone; (5,7-difluoro-H-indol-2-yl) -piperazin-1-yl-methanone; (5,7-difluoro-1 H -indol-2-yl) - (3-methyl-piperazin-1-yl) -methanone; (5,6-difluoro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone and (4,6-difluoro-1 H -indol-2-yl) - (4 -methyl-piperazin-1-yl) -metanone. Other examples of compounds include: 1- (5-phosphor-1 H-indole-2-carbonyl) -4-methyl-piperazine-2-carboxylic acid methyl ester; 4- (5-Chloro-1 H -indole-2-carbonyl) -1-methyl-piperazine-2-carboxylic acid methyl ester; 4- (5-chloro-1 H -indole-2-carbonyl) -1-methyl-piperazine-2-carboxylic acid amide; 1- (5-Chloro-1 H -indole-2-carbonyl) -4-methyl-p-piperazine-2-carboxylic acid amide; 4- (5-Chloro-1 H-indole-2-carbonyl) -1-methyl-piperazine-2-carboxylic acid methylamide; 1- (5-Chloro-1H-indole-2-carbonyl) -4-methyl-piperazine-2-carboxylic acid methylamide; 4- (5-chloro-1 H -indole-2-carbonyl) -1-methyl-piperazine-2-carboxylic acid dimethylamide; 1- (5-Chloro-1H-indole-2-carbonyl) -4-methyl-piperazine-2-carboxylic acid dimethylamide; (5-chloro-1 H-indol-2-yl) - (3-hydroxymethyl-4-methyl-piperazin-1-yl) -methanone; (5-chloro-1 H -indol-2-yl) - (3-methoxymethyl-4-methyl-piperazin-1-yl) -methanone; (5-chloro-1 H-indol-2-yl) - (2-methoxymethyl-4-methyl-piperazin-1-yl) -methanone; (5-Chloro-1 H-indol-2-yl) - (4-methyl-3-methylaminomethyl-piperazin-1-yl) -metanone; (5-chloro-1 H -indol-2-yl) - (4-methyl-2-methylaminomethyl-piperazin-1-yl) -methanone; (5-chloro-1 H -indol-2-yl) - (3-dimethylaminomethyl-4-methyl-piperazin-1-yl) -methanone; and (5-chloro-1 H -indol-2-yl) - (2-d-methylaminomethyl-4-methyl-piperazin-1-yl) -methanone. Examples of preferred compounds include: (5-chloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-fluoro-1 H -indole-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-1H-indoI-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-methyl-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-difluoro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (7-chloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-dichloro-1 H -indol-2-yl) - (4-methylpiperazin-1-yl) -methanone; and (3,5-dichloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone. More preferred compounds in this group include: (5-chloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-methyl-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-difluoro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-fluoro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (7-amino-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (7-methyl-1 H-indol-2-N) - (4-methyl-piperazin-1-yl) -methanone; and (5,7-dichloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone. Additional examples of preferred compounds include (6-chloro-1 H -indole-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (1 H-indol-2-yl) - (3-methyl-plperazin-1-yl) -methanone; (7-bromo-1 H -indole-2-yl) - (4-methyl-p-piperazin-1-yl) -methanone; (5-bromo-benzofuran-2-yl) - (4-methyl-p¡perazin-1-yl) -methanone; and (1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanethione. The most preferred compound is (5-chloro-1 H -indol-2-yl) - (4-methylpiperazin-1-yl) -methanone. The described compounds can be prepared according to the following section.
C. Synthesis The described compounds can be made by combination or traditional organic synthesis methods, as outlined below in Schemes 1-12 and Chemical Examples 1-86, or by analogous reactions.
SCHEME 1
The compounds of the formula III can be prepared from the compounds of the formula II using conventional methods of amide bond formation. For example, the carboxyl group of compound II can be activated as an active ester, acid chloride, anhydride, mixed anhydride, mixed carbon dioxide or the like and can be treated with an amine-containing group to give a compound of formula III. For example, the compound of formula II can be converted to the corresponding active ester under treatment with 1-hydroxybenzotriazole in the presence of carbodiimide, for example dicyclohexylcarbodiimide or 1-ethyl-3- (3'-dimethyl-aminopropyl) -carbodiimide hydrochloride. gives in the presence of a base such as triethylamine or?,? - diisopropylethylamine to give the compound of the formula III. In a preferred embodiment, the compound of formula II is treated with 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, (HATU) and 1-hydroxy-7- azabenzotriazole, (HOAT) and?,? -diisopropylethylamine in a solvent, for example DMF, THF or the like, together with an amine IV component to give a compound of formula III. In a further preferred embodiment, a compound of the formula II can be treated with carbonyldiumidazole (CDI) in a solvent, for example THF, DMF, dichloromethane or the like, followed by an amine IV component to give a compound of the formula III.
SCHEME 2
The compounds of the formula III can be prepared according to Fischer's indole synthesis, which involves the condensation of phenylhidrazine with an aldehyde or ketone to give an intermediate hydrazone. Therefore, a compound of the formula V can be condensed with ethyl pyruvate, generally in the presence of an acid catalyst, for example sulfuric acid to give a hydrazone of the formula VI. The compounds of the formula VI can be converted to the formula VII ings under treatment with a protic or Lewis acid, if required at elevated temperature, to effect cyclization. Examples of acids include: polyphosphoric acid, para-toluenesulfonic acid, pyridine hydrochloride, zinc chloride and phosphorus chloride, trimethylsilyl ester of polyphosphoric acid and acetic acid. Compounds VI can also be converted to compound VII under thermal conditions by heating a compound of formula VI in a solvent, for example ethylene glycol, tetralin, or the like at elevated temperature, for example at about 150 to 250 ° C. One skilled in the art will recognize that the cyclization of compounds of the formula VI to compounds of the formula VII can give rise to isomers when the compounds of the formula V contain substituents. It will further be recognized that the conditions for effecting cyclization may be different for compounds other than formula VI. In a further embodiment, compounds of formula VII can be prepared by condensation of a 2-nitrotoluene appropriately substituted with an oxalate diester in the presence of a base followed by reduction of the intermediate to give a compound of formula VII. In a preferred embodiment, a 2-nitrotoluene is condensed with ethyl pyruvate in the presence of a base such as sodium methoxide, sodium butoxide or sodium ethoxide in a solvent such as ethanol, methanol or butanol. For example, a solution of 2-nitrotoluene in ethanol is heated with ethyl pyruvate in the presence of sodium ethoxide at reflux temperature. The condensation product can be converted to a compound of formula VII using a reducing agent, preferably zinc in aqueous acetic acid. The compounds of the formula VII can be converted to compounds of the formula II using standard methods for ester hydrolysis, for example under treatment with acid or aqueous base, if necessary at elevated temperature. In a preferred embodiment, the hydrolysis can be carried out under treatment with a compound of the formula VII with a solution of lithium hydroxide in an alcohol solvent, preferably ethanol. The compounds of formula II can be converted to compounds of formula III according to the procedures described above.
SCHEME 3
The compounds of the formula IX can be prepared from the compounds of the formula VIII using conventional methods of amide bond formation as described for the preparation of compounds of the formula III for compounds of the formula II by condensation of the carboxylic acid of formula VIII with an amine component IV.
SCHEME 4
The compounds of formula III can be prepared as illustrated in scheme 4. The treatment of an optionally substituted 2-nitrotoluene (formula X) with an oxalate, such as diethyl oxalate, in the presence of a base gives a 2- keto ester of the formula XI. Typical bases used to effect this transformation include potassium ethoxide, sodium hydride and lithium t-butoxide. The reduction of the nitro group of a compound of the formula XI to the corresponding aniline is accompanied by cyclization to the indole-2-carboxylate, a compound of the formula VII. Typical reductants for this transformation include hydrogen on palladium, tin (II) chloride, and sulfur. The compounds of formula VII can be converted to compounds of formula II using standard methods for ester hydrolysis, for example under treatment with an aqueous acid or base, if necessary at elevated temperature. In a preferred embodiment, the hydrolysis can be carried out under treatment with a compound of the formula VII with a solution of lithium hydroxide in THF. The conversion to the VI target compounds is carried out as described in scheme 2. Formulas XII and XIII do not exist in this description.
The compounds of the formula III can also be prepared from compounds of the formula II by condensation of a terbutyl ester of piperazine-1-carboxylic acid of the formula XIV with a compound of the formula II using conventional methods of bond formation. amide as described for the preparation of compounds of the formula III with compounds of the formula II. In a preferred embodiment, a compound of the formula II is treated with carbonylimidazole (CDI) in a solvent, for example THF, DMF, dichloromethane or the like, followed by a terbutyl ester of piperazine-1-carboxylic acid of the formula XIV to give a compound of formula XV. Compound XV can be converted to a compound of formula XVI under treatment with an acid, for example trifluoroacetic acid or hydrochloric acid in a solvent, for example dichloromethane, THF, dioxane or the like. In a preferred embodiment, the acid is trifluoroacetic acid and the solvent is dichloromethane. A compound of the formula III can be obtained from a compound of the formula XVI under treatment with an alkylating agent in the presence of a base. Suitable alkylating agents include alkyl bromides, alkyl chlorides, alkyl iodides, alkyl mesylates and alkyl tosylates. The transformation is carried out in the presence of a base, for example potassium carbonate, sodium hydroxide, triethylamine and the like, in a solvent, for example ethanol, methanol, acetone, dichloromethane, DMF, THF and the like. Preferred conditions use potassium carbonate in acetone. The reaction can be carried out at elevated temperature, preferably at about 50 ° C.
SCHEME 6
The compounds of the formula XVIII can be prepared from the compounds of the formula XVII according to known methods for the functionalization of the indole group in C-3. Such methods include, but are not limited to halogenation, for example treatment with a halogen source in a solvent, for example under treatment with bromine in acetic acid, N-chlorosuccinamide, N-bromosuccinamide, N-yodosuccinamide in dichloromethane, carbon tetrachloride. , chloroform or the like; formylation, for example by heating a DMF solution of a compound of formula XVII with phosphorus oxychloride (Vilsmeier-Haack conditions); aminoalkylation, for example, by treating a compound of formula XVII with a mixture of an amine and a formaldehyde source (Mannich conditions). One skilled in the art will recognize that not all electrophilic in-ring reactions will lead to substitution at C-3 alone and additional substitution can also take place and those product mixtures can be obtained. In addition it will be recognized that the products of the substitution reactions (3-substituted idols) can be used for further transformations.
SCHEME 7
A compound of the formula XX can be obtained from a compound of the formula XIX under treatment with 2,4-bis (4-methoxy-phenyl) -1,2,2,4-dithiadiphosphetane 2,4-disulfide ( also known as Lawesson's reagent) in a solvent such as ether, THF or dioxane. In a preferred embodiment, the compound of formula XIX is treated with Lawesson's reagent in THF to give a compound of formula XX.
SCHEME 8
A compound of formula XXI can be obtained from a compound of formula XIX using conventional methods for reduction of amide bond. For example using lithium hydride, aluminum in THF, magnesium hydride, aluminum in THF, lithium trimetoxyalumium hydride, bis (2-methoxyethoxy) -aluminum hydride of sodium, alane in THF and borane or borane-sulfide complex of dimethyl in THF. A preferred method is the use of lithium-aluminum hydride in a solvent, for example THF, dioxane, ether or the like at 25 ° C up to the boiling point of the selected solvent. In a more preferred embodiment, the reducing agent is lithium aluminum hydride in THF at reflux temperature. As shown in the following scheme, compounds of formula XI can be prepared using a Phillip-like reaction involving the condensation of an ortho-arylenediamine with a carboxylic acid or the like, to generate the benzimidazole nucleus.
SCHEME 9
Accordingly, a compound of the formula XXII can be condensed with a glycolic acid and typically with an acid catalyst, for example hydrochloric acid, to give compounds of the formula XXIII. One skilled in the art will recognize that the condensation of compounds of the formula XXII to compounds of the formula XXIII can give rise to isomers when the compounds of the formula XXII contain substituents. The compounds of the formula XXIII can be oxidized with a suitable oxidizing agent to give compounds of the formula X. The oxidants can include potassium permanganate, chromium dioxide, sodium hypochlorite, methyl sulfoxide with oxalyl chloride, manganese dioxide or any combination of them. The compounds of the formula X can be converted to compounds of the formula XI according to the processes described above for compounds of the formula II by condensation of the appropriate carboxylic acid of the formula X with an amine IV component.
Scheme 10 illustrates methods for making substituted proximal and distal regioisomers. Analogous methods may be used with other rings other than 6 members, such as 5 or 7 membered rings. Further modifications can be made to change the hydroxymethyl and methyl ester substituents using methods well known to those skilled in the art, including but not limited to those methods detailed in Schemes 11 and 12. The 2-methyl ester of 4-ter-ester 1-benzyl ester of peperazin-1, 2,4-tricarboxylic acid can be prepared according to the procedure of Bigge et al. . { Tetrahedron Lett. 30: 5193-5 96, 1989). Selective deprotection of the CBz group or the BOC group can be achieved using standard methods. For example, selective removal of the CBz group of the 2-methyl ester of 4-tert-butyl ester of 1-benzyl ester of piperazin-1, 2,4-tricarboxylic acid can be achieved under treatment with but not limited to H2 and Pd / C or ammonium formate and PD / C in solvents such as ethanol or ethyl acetate or the like, to give 3-methyl ester of 1-tert-butyl ester of piperazin-1,3-dicarboxylic acid. The conversion of 3-methyl ester of 1-tert-butyl ester of piperazin-1,3-dicarboxylic acid to 3-methyl ester of 1-tert-butyl ester of 4-methyl-piperazin-1,3-dicarboxylic acid it can be achieved using standard conditions for reductive animation. These include but are not limited to treatment with paraformaldehyde in the presence in the presence of a reducing agent such as sodium borohydride., sodium cyano borohydride or sodium triacetoxy borohydride or the like, in a solvent such as tetrahydrofuran, methanol, ethanol, 1,2-dichloroethane, trifluoroethanol or the like. One skilled in the art will recognize that the addition of acid to reduce the pH of the reaction mixture to a pH of less than about 7 may be necessary to effect the reaction, wherein the acid is added as necessary and is such as acetic acid , hydrochloric acid and the like. Preferred reducing agents are sodium cyano borohydride or sodium triacetoxy borohydride. The removal of the BOC group can be achieved under treatment with an acid, for example trifluoroacetic acid or hydrochloric acid in a solvent, for example dichloromethane, THF, dioxane or the like to give acid methyl ester
1 - . 1-methyl-piperazine-2-carboxylic acid. The reduction of the methyl ester can be achieved by standard conditions which include but are not limited to treatment with reducing agents such as lithium-aluminum hydride or diisobutyl aluminum hydride or the like, in solvents such as THF or diethyl ether or the like to give (1) -methyl-piperazin-2-yl) -methanol. Alternatively, the selective removal of the ester BOC group
2-methyl ester of 1-benzyl ester of piperazin-1, 2,4-tricarboxylic acid can be achieved under treatment with an acid, for example trifluoroacetic acid or hydrochloric acid in a solvent, for example dichloromethane, THF, dioxane or the like to give 2-methyl ester of 1-benzyl ester of piperazin-1,2-dicarboxylic acid. The conversion of 2-methyl ester of 1-benzyl ester of piperazin-1,2-dicarboxylic acid to 2-methyl ester of 1-benzyl ester of 4-methyl-piperazin-1,2-dicarboxylic acid can be achieved using standard conditions for reductive amination. These include but are not limited to treatment with paraformaldehyde in the presence of a reducing agent such as sodium borohydride, sodium cyano borohydride or sodium triacetoxy borohydride or the like, in a solvent such as tetrahydrofuran, methanol, ethanol, 1,2-dichloroethane , trifluoroethanol or similar. One skilled in the art will recognize that the addition of acid to reduce the pH of the reaction mixture to a pH of less than about 7 may be necessary to effect the reaction, wherein the acid is added as necessary and is such as acetic acid , hydrochloric acid or similar. Preferred reducing agents are sodium cyano borohydride or sodium triacetoxy borohydride. The removal of the CBz group from this 2-methyl ester of 1-benzyl ester of 4-methyl-piperazin-1,2-dicarboxylic acid can be achieved under treatment with but not limited to H2 and Pd / C or ammonium formate Pd / C in solvents such as ethanol or ethyl acetate or the like, to give 4-methyl-piperazine-2-carboxylic acid methyl ester. Reduction of the methyl ester can be achieved using standard conditions including but not limited to treatment with reducing agents such as lithium-aluminum hydride or diisobutylaluminum hydride or the like, in solvents such as THF or diethyl ether or the like to give (4-methyl) -piperazin-2-yl) -methanol.
SCHEME 11
The compounds of formulas XXIV and XXVII can be prepared from compounds of formula II using conventional methods of amide bond formation, as described for the preparation of compounds of formula III from compounds of formula II, by condensation of the appropriate carboxylic acid of formula II with an amine component such as those described in scheme 10. Schemes 11 and 12 illustrate non-limiting methods for providing substituted rings, such as the substituted piperazines shown in compounds XXVI and XXIX. For scheme 1, hydrolysis of the ester can be achieved using standard methods for ester hydrolysis, for example under treatment with acid or aqueous base, if necessary at elevated temperature. The compounds of the formula XXVI wherein Y is nitrogen can be prepared using conventional methods of amide bond formation, as described for the preparation of compounds of the formula III from the compounds of the formula II, by condensation of the acid carboxylic acid of the formula XXV with an amine component, suitable. Compounds of formula XXVI wherein Y is oxygen can be prepared using conventional methods of ester formation such as but not limited to conversion of the acid chloride using reagents such as oxalyl chloride or the like, followed by treatment with an appropriate alcohol. For scheme 12, compounds of formula XXVIII can be prepared from compounds of formula XXVII using conventional methods such as but not limited to treatment with triphenylphosphine and carbon tetrabromide, thionyl bromide or HBr. The compounds of the formula XXVIII may be treated with alcohols or amines to give compounds of the formula XXIX wherein Y is oxygen or nitrogen respectively, possibly in the presence of a suitable base such as but not limited to cesium carbonate or triethylamine.
D. Uses In accordance with the invention, the compounds and compositions described are useful for the relief of symptoms associated with the following conditions and diseases: inflammatory disorders, asthma, atherosclerosis, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, intestinal disease inflammatory, multiple sclerosis, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders, as well as the treatment and prevention thereof. The disclosed compounds may also be useful as adjuvants in chemotherapy or in the treatment of itchy skin. The invention also relates to pharmaceutical compositions including, without limitation, one or more of the disclosed compounds, and a pharmaceutically acceptable carrier or excipient. Aspects of the invention include (a) a pharmaceutical composition comprising a compound of the formula (I) or (Ib), or one or more preferred compounds as described herein, and a pharmaceutically acceptable carrier; (b) a packaged drug comprising (1) a pharmaceutical composition comprising a compound of claim 1, 2 or 3 and a pharmaceutically acceptable carrier, and (2) instructions for the administration of said composition for the treatment or prevention of a disease or condition mediated by H.
The invention also provides a method for treating a condition mediated by H 4 in a patient, said method comprising administering to a patient a pharmaceutically effective amount of a composition comprising compounds of the formula (I) or (Ib) or other compounds described or preferred. For example, the invention relates to a method for the treatment of a condition mediated by H 4 in a patient, said method comprises administering to the patient a pharmaceutically effective H 4 antagonizing amount of a composition comprising a compound of the formula (I ) or (Ib) or other described or preferred compounds. The effect of an antagonist can also be produced by means of an inverse agonist. Reverse agonism describes the property of a compound to actively turn off a receptor that displays constitutive activity. The constitutive activity can be identified in cells that have been forced to overexpress the human H4 receptor. The constitutive activity can be measured by examining cAMP levels or by measuring a reporter gene responsive to cAMP levels after treatment with a cAMP stimulating agent such as forskolin. Cells that overexpress H4 receptors will exhibit lower cAMP levels after treatment with forskolin than cells that do not express it. Compounds that behave as H4 agonists will dose-dependently reduce cAMP levels stimulated by Forskolin in cells expressing H4. Compounds that behave as inverse H4 agonists will dose-level stimulate cAMP levels in cells expressing H4. Compounds that behave as H4 antagonists will block either the AMPc inhibition induced by H4 agonist or increases in cAMP induced by H4 agonist. Additional embodiments of the invention include disclosed compounds that are inhibitors of a mammalian histamine H4 receptor function, inhibitors of inflammation or inflammatory responses in vivo or in vitro, modulators of the expression of a mammalian histamine H4 receptor protein. inhibitors of polymorphonuclear leukocyte activation in vivo or in vitro, or combinations of the above, and corresponding treatment, prophylaxis and diagnosis methods comprising the use of a described compound.
1. Dosage Those skilled in the art will be able to determine, according to known methods, the appropriate dose for a patient, considering factors such as age, weight, general health, the type of symptoms that require treatment., and the presence of other medications. In general, an effective amount will be between 0.01 and 1000 mg / kg per day, preferably between 0.5 and 300 mg / kg of body weight, and daily doses will be between 10 and 5000 mg for an adult subject of normal weight. Capsules, tablets or other formulations (such as liquids and film-coated tablets) can be between 0.5 and 200 mg, such as 1, 3, 5, 10, 15, 25, 35, 50 mg, 60 mg, and 100 mg they can be administered according to the methods described.
2. Formulations Dose unit forms include tablets, capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted to be subdivided into individual doses. Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. Methods of administration include oral, rectal, parenteral, (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels or creams), and by inhalation (a buccal or nasal spray) . The parenteral formulations include aqueous or non-aqueous solutions, dispersions, suspensions, emulsions and sterile powders for the preparation thereof. Examples of vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils and injectable organic esters such as ethyl oleate. The fluidity can be maintained by the use of a coating such as lecithin, a surfactant or by maintaining the appropriate particle size. Vehicles for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption accelerators, (g) adsorbants, (h) lubricants, (i) pH regulating agents, and (j) propellants. The compositions may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersants; antimicrobial agents such as parabens, chlorobutanol, phenol and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption enhancing agents such as aluminum monostearate and gelatin; and absorption enhancing agents.
3. Related Compounds The invention provides the described compounds and pharmaceutically acceptable, closely related forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; covered or protected forms; and racemic mixtures, or enantiomerically or optimally pure forms. Pharmaceutically acceptable salts, esters and amides include carboxylate salts (eg, Ci-8 alkyl, cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclic, acid addition salts of amino, esters, and amides which are within the ratio reasonable risk / benefit, pharmacologically effective and suitable to make contact with the patient's tissues without toxicity, irritation, or allergic response Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate Stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, giucoheptonate, lactiobionate and lauryl sulphonate These may include alkali metal and alkaline earth metal cations such as sodium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium and amine cations such as tetramethylammonium, methylamine, trimethylamine and tilamine, see, for example, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. ScL, 1977, 66: 1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary alkylamines of C-6 and di (C 1-6 alkyl) secondary amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring portions containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, primary amines of C1_3alkyl and di (C1_2alkyl) amines. Representative pharmaceutically acceptable esters of the invention include C1-7 alkyl esters, C5-7 cycloalkyl, phenyl, and phenyl-alkylamino (Ci-6). Preferred esters include methyl esters. The invention also includes disclosed compounds having one or more functional groups (eg, hydroxyl, amino or carboxyl) covered by a protecting group. Some of these covered or protected compounds are pharmaceutically acceptable; others will be useful as intermediaries. The synthetic intermediates and methods described herein, and minor modifications thereof, are also within the scope of the invention.
Hydroxyl protecting groups The protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers and silyl ethers.
Examples of substituted methyl ethers include substituted methyl ethers metioximetilo, methylthiomethyl, t-butylthiomethyl, (fenildimetilosilil) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) met¡lo, guaiacolmetilo, f-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2 -methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methylo, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl , S, S-4-methoxytetrahydrothiopyranyl dioxide, 1 [(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl, 1,4-d-oxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
Substituted ethyl ethers Examples of substituted ethyl ethers include 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy- 2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.
Ethers Examples of substituted benzyl ethers substituted include benzyl p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halogenobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4- picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl,?,? -dinitrobenzhidrilo, 5-dibenzosuberyl, triphenylmethyl, -naftildifenilmetilo, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-metoxifen¡l) methyl, 4- (4'-bromofenacilox¡) -feniidifenilmetilo, 4,4' , 4"-tris (4,5-dichlorophthalimidophenyl) methyl J 4,4 ', 4" -tris (levulinoyloxyphenyl) methyl, 4,4', 4"-tris (benzoyloxyphenyl) methyl, 3- (midazole -1-methylmethyl) bis (4 ', 4"-dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1' -phenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9 phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl and S, S-benzisothiazolyl dioxide.
Silyl ethers Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl-xylynylsilyl, t-butyldimethylsilyl, f-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylsilyl, triphenylsilyl, diphenylmethylsilyl, and -butylmethoxyphenylsilyl.
Esters In addition to ethers, a hydroxyl group can be protected as an ester. Examples of esters include formate, benzoyl, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, pP-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- ( ethylendithio) pentanoate, pivaloate, adamanthoate, crotonate, 4-methoxyrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate)
Carbonates Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonium) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl and methyl dithiocarbonate.
Examples of assisted power division division includes 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formilbencensulfonato carbonate, 2- (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) butyrate, and 2- (methylthiomethoxymethyl) benzoate.
Miscellaneous Esters Examples of various esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1-, 3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1, 1 - dimetilprop¡l) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenoate (tigloate), o- (methoxycarbonyl) -? benzoate, p -P-benzoate, a-naphthoate, nitrate, alkyl, ? ',?' - tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl and 2,4-dinitrofenyl sulfenate.
Sulfonates Examples of sulfonates include sulfate, methanesulfonate- (mesylate), benzylsulfonate and tosylate.
Protection for 1, 2- and 1, 3-diols
Acétals and cyclic ketals Examples of cyclic ketals and ketals include methylene, ethylidene, 1-t-butylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), p-methoxybenzylidene, , 4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene and 2-nitrobenzylidene.
Ortho-cyclic esters Examples of cyclic ortho esters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, α-methoxybenzylidene, 1 - (N, N-dimethylamino) ethylidene derivative, a- (N, N-dimethylamino) benzylidene, and 2-oxacyclopentylidene.
Silyl Derivatives Examples of silyl derivatives include di-f-butylsilylene group, and 1,3- (1,1-, 3,3-tetraisopropyldisiloxaneidene) derivative.
Amino-protecting group The protection for the amino group includes carbamates, amides and special protective -NH groups. Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, partitioned carbamates, photolytic cleavage carbamates, various urea derivatives and carbamates.
Carbamates Examples of methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fIuorenilmetiio, 9- (2,7-dibromo) fluorenylmethyl, 2,7-di-f-butyl- [9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl) methyl and 4-methoxy-phenacyl.
Substituted Ethyl Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-halogenoethyl, , 1-dimethyl-2,2-dibromoetyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-di-1) -butylphenyl) -1-methylethyl, 2- (2'- and 4'-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl , 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, aikyildithium, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.
Assisted Division Examples of assisted division include 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl , 2-phosphononoethyl, 2-triphenylphosphonium isopropyl, 1,1-dimethyI-2-cyanoethyl, / D-chloro-p-acyloxybenzyl, p- (dihydroxyboronyl) benzyl, 5-benzisoxazolylmethyl, and 2- (trifluoromethyl) -6- chromonylmethyl.
Photolithic division Examples of photolithic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl (or nitrophenyl) methyl.
Urea-type derivatives Examples of urea-type derivatives include phenothiazinyl- (10) -carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl and N'-phenylamino-thiocarbonyl.
Miscellaneous Carbamates Examples of various carbamates include t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) benzyl, 1, 1-dimethyl-3- (N, N-dimethylcarboxamido) -propyl, 1, 1-dimethylpropynyl, di (2-pyridyl) metiIo, 2-furamlmetilo, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p- (p'-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1 -ciclopropilmetilo, 1-methyl-1- (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-phenylazophenyl) ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri-f-butylphenyl, 4- (trimethylammonium) benzyl , and 2,4,6-trimethylbenzyl.
Examples of amides include:
Amides N-form¡lo, N-acetyl, N-chloroacetyl, N-trichloroacetyl, trifluoroacetyl N, N-feniloacetilo,? -3-phenylpropionyl, N-picolinoyl, N-3 piridilocarboxamida, N-benzoylphenylalanyl derivative, N-benzoyl , Np-phenylbenzoyl.
Non-assisted Division nitrophenylacetyl, No-nitrophenoxyacetyl, N-acetoacetyl, ( '- dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl, N-3- (o- nitrophenyl) propionyl, N-2-met¡ l-2- (naryophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) propionyl, 4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-nitrocinnamoyl , derivative of N-acetylmethionine, No-nitrobenzoyl, No- (benzoyloxymethyl) benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
Derivatives of cyclic measure N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrryoyl, adduct of N-1, 1,4,4-tetramethyldisilylazacyclopentane, 1,3 -dimethyl-1, 5-substituted 3,5-triazacyclohexan-2-one, 1,3-dibenzyl-1, 3,5-triazacyclohexan-2-one 5-substituted, and 3,5-dinitro-4-pyridonyl 1 -replaced.
Examples of special NH protecting groups include
N-alkyl and N-aryl amines N-methyl, N-allyl, N- [2- (trimethylsilyl) ethoxy] methyl,? -3-acetoxypropyl,
N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di (4-methoxyphenyl) methyl,? -5-dibenzosuberl , N-triphenylmethyl, N- (4-methoxyphenyl) diphenylmethyl,? -9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N'-oxide of? -2-picolylamine.
Derivatives of N-1-mine, 1-dimethylthiomethylene, N-benzylidene, N-methoxybenzylidene, N-diphenylmethylene, N - [(2-pyridyl) mesyl) methylene and N- (N ', N'-dimethylamino-methylene).
Protection for the carbonyl group
Acetals and acyclic ketals Examples of acyclic ketals and ketals include dimethyl, bis (2,2,2-trichloroethyl), dibenzyl, bis (2-nitrobenzyl) and diacetyl.
Acétals and cyclic ketals Examples of acétals and cyclic ketals include 1,3-dioxanes, 5-methylene-1,3-dioxane, 5,5-dibromo-1,3-d-oxane, 5- (2-p) ridyl) -1, 3-dioxane, 1, 3-. dioxolanes, 4-bromomethyl-1,3-dioxolane, 4- (3-butenyl) -1, 3-dioxolane, 4-phenyl-1,3-dioxolane, 4- (2-n-phenylphenyl) -1, 3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,?,? '- phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepine.
Acyctal acetals and acetals Examples of acyclic dithioacetals and ketals include S, S'-dimethyl, S, S'-diethyl, S, S'-dipropyl, S, S'-dibutyl, S, S'-dipentyl, S, S '-diphenyl, S, S'-dibenzyl and S.S'-diacetyl.
Ditio cyclic acetals and cyclic examples Examples of cyclic dithioacetals and ketals include 1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzoditiepin.
Monothio acetals and acyclic ketals Examples of acyclic monothioacetals and ketals include O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl and 0-methyl-S-2- (methylthio) ethyl.
Monothio acetals and cyclic ketals Examples of monothioacetals and cyclic ketals include 1,3-oxathiolanes.
Miscellaneous derivatives
O-substituted cyanohydrins Examples of O-substituted cyanohydrins include O-acetyl, O-trimethylsilyl, β-1-ethoxyethyl and O-tetrahydropyranyl.
Substituted Hydrazones Examples of substituted hydrazones include α, β-dimethyl and 2,4-dinitrophenyl.
Oxime derivatives Examples of oxime derivatives include O-methyl, O-benzyl and O-phenylthiomethyl.
Films
Substituted methylene derivatives, cyclic derivatives Examples of substituted methylene derivatives and cyclics include oxazolidines, 1-methyl-2- (1-hydroxyalkyl) imydazoles,?,? '- dimethylimidazolidines, 2,3-dihydro-1, 3-benzothiazoles, adducts of diethylamine, and methylaluminum complex bis (2,6-di-f-butyl-4-methylphenoxide) (MAD).
Monoprotection of dicarbonyl compounds
Selective protection of - and ß-diketones Examples of selective protection of a- and ß-diketones include enamines, enolacetates, methyl, ethyl, / -butyl, piperidinyl, morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl and tyrimethylsilyl.
Cyclic, monomial and dithio-ketal cetals Examples of cyclic, monomial and dithio-ketal ketals include bis-methylenedioxy derivatives and tetramethyl-bis-methylenedioxy derivatives.
Portion for the carboxyl group
Esters
Substituted methyl esters Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl and N-phthalimidomethyl.
2-Substituted ethyl esters Examples of substituted ethyl esters include 2,2,2-trichloroethyl, 2-halogenoethyl, β-chloroalkyl, 2- (trimethylsilyl) ethyl, 2-methylthioethyl, 1,3-dithionyl- 2-methyl, 2- (p-nitrophenylsulphenyl) ethyl, 2- (p-toluenesulfonyl) ethyl, 2- (2'-pyridyl) ethyl, 2- (diphenylphosphine) ethyl, 1-methyl-1-phenylethyl, -butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1 -yl, cinnamyl, a-methylcinnamyl, phenyl, p- (methylmercapto) phenyl and benzyl .
Substituted benzyl esters Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2- (9,10-dioxo) anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2- (trifluoromethyl) - 6-chromium, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4- (methylsulfinyl) benzyl, 4-sulfobenzyl, piperonyl , 4-picolyl and pP-benzyl.
Silyl esters Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, / '-propyldimethylsilyl, phenyldimethylsilyl and di-t-butylmethylsilyl.
Activated esters Examples of activated esters include thiols.
Miscellaneous Derivatives Examples of various derivatives include oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt complex (III).
Esters are nil ics Examples of stanyl esters include triethyl ethanyl and tri-r? -butyl ethanyl.
Amides Examples of amides include?,? - dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides,? -7-nitroindolyl,? -8-nitro-1, 2,3,4-tetrahydroquinolyl and pP-benzenesulfonam you give.
Hydrazides Examples of hydrazides include N-phenyl and?,? '-diisopropyl hydrazides.
E. Chemical examples
EXAMPLE 1 K¡ = 0.005 μ?
(5-Chloro-H-indol-2-yl) - (4-methyl-piperazin-1 -iQ-methanone)
A mixture of 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g) and N, N-dusopropylethylamine (0.191 ml) in DMF (0.6 ml) was treated with N-methylpiperazine ( 0.1 ml) was stirred at room temperature for 48 h, then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (3-10% 2M ammonia in methanol / dichloromethane) to give the title compound (0.18 g). H NMR (400 MHz, CDCl 3): d 9.60 (br s, 1H), 7.65 (d, J = 1.5 Hz, 1 H), 7.40 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 7.26 (d, 1.8 Hz, 1 H), 6.76 (d, J = 1.5 Hz, H), 4.0 (br m, 4 H), 2.56 (t, J = 5.1 Hz, 4 H), 2.41 (s, 3H). Analysis calculated for C 4 H 16 CIN 30; C, 60.54; H, 5.81; N, 15.13; Found: C, 59.99; H, 5.94; N, 18.87. The title compounds of the following examples (2-14) were prepared according to the general procedure of scheme 1, as indicated for example 1.
EXAMPLE 2 K¡ 0.018 μ?
(5-Fluoro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
1 H NMR (400 MHz, CDCl 3): d 9.70 (br s, 1 H), 7.33 (m, 2 H), 7.09-6.98 (m, 1 H), 6.75 (m, 1 H), 3.97 (br m, 4 H ), 2.53 (dm, J = 4.7 Hz, 4H), 2.38 (s, 3H).
EXAMPLE 3 Kj = 0.008 μ?
(5-Bromo-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
H NMR (400 MHz, CDCl 3): d 9.65 (br s, 1 H), 7.78 (d, J = 1.0 Hz, 1 H), 7.40-7.26 (m, 2H), 6.73 (d, J = 2.3 Hz, 1 H), 3.97 (br m, 4H), 2.53 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H).
EXAMPLE 4 K¡ = 0.11 17 μ?
(1 H-lndol-2-yl) - (4-methyl-piperazin-1-ii) -metanone
H NMR (400 MHz, CDCl 3 CD 3 OD): d 7.63-7.56 (m, 1 H), 7.40 (dt, J = 1.0, 8.3 Hz, 1 H), 7.26-7.20 (m, 1 H), 7.1 1-7.05 ( m, 1 H), 6.99 (d, J = 0.8 Hz), 6.72 (d, J = 0.8 Hz), 3.88 (br m, 4H), 2.48 (t, J = 5.1 Hz, 4H), 2.31 (s, 3H).
EXAMPLE 5 K¡ = 7 μ?
(5-Benzyloxy-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
EXAMPLE 6 K¡ = 0.01 1 μ?
(5-Methyl-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
H NMR (400 MHz, CDCl 3): d 8.91 (br s, 1H), 7.34 (dm, J = 0.7
Hz, 1H), 7.24 (d, J = 8.3 Hz, 1 H), 7.04 (dd, J = 8.3, 1.3 Hz, 1 H), 6.62 (dd, J = 2.0, 0.8 Hz, 1H). 3.88 (br m, 4H), 2.44 (t, J = 4.0 Hz, 4H), 2.37 (s, 3H), 2.29 (s, 3H).
EXAMPLE 7 K¡ = 10μ?
(5,6-D-methoxy-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
EXAMPLE 8 Kj = 2 μ?
(4-Methyl-piperazin-1-yl) - (7-nitro-1H-indol-2-yl) -metanone
H NMR (400 MHz, CDCl 3): d 10.46 (brs, 1H), 8.29 (, d, 1H), 8.06
(d, 1H), 7.34 (m, 1H), (t, 1H), 3.94 (br m, 4H), 2.54 (t, 4H), 2.40 (s, 3H).
EXAMPLE 9 K¡ = 10 μ?
(4-Methyl-piperazin-1-yl) - (5-nitro-3-phenyl-1 H-indol-2-yl) -methanone EXAMPLE 10 K = 1.7 μ
(4-Methyl-piperazin-1-yl) - (5-trifluoromethoxy-1H-indol-2-yl) -metanone
EXAMPLE 11 K¡ = 0.124 μ?
(6-Chloro-1 H-indol-2-H) - (4-methyl-piperazin-1-yl) -metanone
1 H NMR (400 MHz, CDCl 3): d 10.14 (br s, 1 H), d 7.55 (d, J = 8.3 Hz, 1 H), 7.44 (t, J = 1.0 Hz, 1 H), 7.10 (dd, J = 8.3, 1.8 Hz, 1 H), 6.76 (dd, J = 2.3, 1.0 Hz, IH), 4.00 (br m, 4H), 2.54 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H ). MS: exact mass calculated for C14H 6CIN30, 277.10; m / z found, 278.1 [M + H] +.
EXAMPLE 12 Kj = 0.019 μ?
(5J-Difluoro-1 H-indol-2-yl) - (4-metn-piperazin-1-yl) -metanone
1 H NMR (400 MHz, CDCl 3): d 9.94 (br s, H), 7.10 (dd, J = 8.8, 2.0 Hz, 1 H), 6.87-6.78 (m, 1 H), 6.77 (t, J = 2.8 Hz, 1 H), 3.97 (br m, 4 H), 2.53 (t, J = 5.1 Hz, 4 H), 2.37 (s, 3 H).
MS: exact mass calculated for Ci 4 H 5 F 2 N 30, 279.12; m / z found, 280 [M + H] +.
EXAMPLE 13 K¡ = 0.235 μ?
(6-Fluoro-1H-indol-2-yl) - (4-methyI-piperazin-1-yl) -metanone
1 H NMR (400 MHz, CDCl 3): d 9.45 (br s, 1 H), 7.49 (dd, J = 8.8, 1 H), 7.02 (dd, J = 9.4, 2.3 Hz, 1H), 6.87-6.81 (m , 1 H), 6.69 (dd, J = Hz, 1 H), 3.89 (br m, 4H), 2.44 (t, J = 5.1 Hz, 4H), 2.88 (s, 3H).
EXAMPLE 14 K¡ = 3 μ?
^^ - Dichloro-IH-indol ^ -iD ^ -methyl-piperazin-l-iD-methanone EXAMPLE 15 K¡ = 2 μ?
(1 H-indol-2-yl) - (4-octyl-piperazin-1-yl) -metanone
2-carbohydric acid (0.193 g) in THF (25 ml) was treated with carbonyldiimidazole (0.178 g) and stirred at room temperature for 2 hr after which 1-octyl-piperazine (0.142 g) was added. The mixture was stirred at room temperature for 18 hr, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate, and the organic portion was separated, dried over sodium sulfate and filtered. The solvent was evaporated to give the title compound (0.28 g). 1 H NMR (400 MHz, CD 3 OD): d 7.50 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 7.13-7.09 (m, 1 H), 6.98-6.94 ( m, 1 H), 6.71 (s, 1 H), 3.79 (s, 4H), 2.46 (t, J = 4.7 Hz, 4H), 2.32 (t, J = 7.7 Hz, 2H), 1.46 (br s, 2H), 1.36-1.03 (m, 12H), 0.82-0.79 (m, 3H). The title compounds of the following examples (16-38) were prepared according to the general procedure of the scheme, as indicated for example 15.
EXAMPLE 16 K¡ = 3 μ?
f4-Ethyl-piperazin-1-yl) - (1 H -indole-2-yl) -methanone EXAMPLE 17 K = 5 μ?
(1H-indol-2-yl) - (4-isopropyl-piperazin-1-yl) -methanone EXAMPLE 18 K = 5 μ?
r4- (3-Dimethylamino-propyl) -piperazin-1 -yl) - (1 H -indol-2-yl) -methanone EXAMPLE 19 K = 7 μ?
(4-Butyl-piperazin-1-yl) - (1H-8ndol-2-iQ-methanone EXAMPLE 20 K = 7 μ?
(4-Cyclopentyl-p-piperazin-1-yl) - (1 H -indol-2-yl) -methanone EXAMPLE 21 K = 7 μ?
(1H-indol-2-yl) - (4-phenethyl-piperazine-1 -D-methanone EXAMPLE 22 Kr 7 μ?
(1 H-lndol-2-yl) -r4- (2-piper8din-1-yl-ethyl) -piperazin-1-yl-methanone EXAMPLE 23 Ki = 8 μ?
r4- (2-Ethoxy-ethyl) -piperazin-1-W- (1 H-indol-2-yl) -metanone EXAMPLE 24 K = 8 μ?
(4-sec-Butyl-piperazin-1-yl) -f 1 H -indole-2-yl) -methanone EXAMPLE 25 K = 8 μ?
G4- (1-Ethyl-propyl) -piperazin-1 -? '? - (1 H -indol-2-yl) -metanone
EXAMPLE 26 K¡ = 8 μ?
(1 H-indol-2-yl) -r4- (3-phenyl-propyl) -piperazin-1-yl-methanone
EXAMPLE 27 K¡ = 8 μ?
lndol-2-yl) -r4- (1-methyl-piperidin-4-yl) -piperazin-1-β-methanone EXAMPLE 28 K = 8 μ?
r4- (2-D-Propylamine-ethyl) -piperazin-1-in- (1H-indol-2-yl) -metanone
EXAMPLE 29 K¡ = 10 μ?
(1 H-indol-2-yl) -r4-f3-phenyl-allyl) -p! Perazin-1 -ill-methanone
EXAMPLE 30 K¡ = 9 μ?
2) 4 ?? 3
(1 H-lndol-2-yl) - (4-pentyl-p-piperazin-1-yl) -methanone EXAMPLE 31 K = 9 μ?
(4-Heptyl-p-piperazin-1-H) - (1H-indol-2-yl) -methanone EXAMPLE 32 K = 9 μ?
r4- (2-Diethylamino-ethyl) -piperazin-1-in- (1H-indol-2-yl) -methanone EXAMPLE 33 Ki = 9 μ?
H2) 4OCH3 (1 H-lndol-2-yl-4- (4-methoxy-butyl) -piperazin-1 -n-methanone EXAMPLE 34
(4-Allyl-piperazin-1 H -indole-2-yl) -metanone EXAMPLE 35 K = 9 μ?
r4-f2-Dimethylamino-etl) -piperazin-1-n- (1 H -indol-2-yl) -methanone EXAMPLE 36 K = 10?
(1 H -indole-2H?) - G4 -? - methyl-piperidin-3-yl) -piperazin-1-yl-methanone EXAMPLE 37 KI = 0.1 μ?
(1 H-lndol-2-yl) -f3-methyl-piperazin-1-l) -metanone
1 H NMR (400 Hz, CDCl 3): d 9.16 (s, 1 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.30-7.25 (m, 1 H), 7.14 (t, J = 7.2 Hz, 1H), 6.77 (s, H), 4.59 (m, 2H), 3.10 (m, 1H), 2.94-2.86 (m, 2H), 1.65 (s, 3H), 1.14 (d, J = 5.6 Hz, 3H).
EXAMPLE 38 K¡ = 10 μ?
(1 -Methyl-1 -1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
H NMR (400 MHz, CDCl 3): d 7.64 (dt, J = 1.0, 7.8 Hz, H), 7.38 (dd, J = 8.3, 0.8 Hz, 1H), 7.35-7.32 (m, 1H), 7.19-7.14 (m, 1H), 6.62 (d, J = 0.8 Hz, 1 H), 3.68 (s, 3H), 3.83 (br m, 4H), 2.49 (br m, 4H), 2.37 (s, 3H).
EXAMPLE 39 Kj = 0.023 μ?
(7-Chloro-1 H-indol-2-yl) - (4-methyl-p-piperazin-1-yl) -metanone
2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 ml) was treated with ethyl pyruvate (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at room temperature for 5 minutes and treated with poiiphosphoric acid (0.5 g). The mixture was heated to reflux temperature for 24 hours after which additional polyphosphoric acid (0.5 g) was added and heating was continued for a further 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer was adjusted to neutrality by the addition of a saturated solution of sodium bicarbonate. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (5-10% ethyl acetate / hexane) to give 7-chloro-1 H-indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 ml) followed by water (3 ml) and stirred at room temperature for 18 hours. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give 7-chloro-1 H-indole-2-carboxylic acid (0.089 g). This material (0.089 g) was treated with HATU (0.259 g), HOAT (0.093 g), N, N-diisopropylethylamine (0.158 ml) and N-methylpiperazine (0.05 ml) in DMF (0.6 ml) and stirred at room temperature. environment for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium bicarbonate solution and then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (2-10% 2M ammonia in methanol / dichloromethane) to give the title compound (0.56 g). 1 H NMR (400 MHz, CDCl 3: d 9.17 (br s, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 7.21 (dd, J = 7.6, 0.8 Hz, 1 H), 7.01 (t, J = 7.8 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 3.88 (br m, 4H), 2.45 (t, J = 5.1 Hz, 4H), 2.29 (s, 3H). Title compounds of the following examples (40-43) were prepared according to the general procedure of scheme 2, as indicated for example 39.
EXAMPLE 40 K¡ = 0.010 μ?
(5 J-dichloro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
1 H NMR (400 MHz, CDCl 3): d 9.08 (br s, 1 H), 7.36 (dd, J = 1.8, H), 7.12 (d, J = 1.8 Hz, 1 H), 6.56 (d, J = 2.3 Hz, 1 H), 3.77 (br m, 4H), = 5.1 Hz, 4H), 2.20 (s, 3H).
EXAMPLE 41 K¡ = 0.040 μ?
(4-Bromo-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
EXAMPLE 42 K¡ = 0.188 μ?
(6-Bromo-1 H-indol-2-yl) - (4-methyl-piperazin-1-iU-methanone
1 H NMR (400 MHz, CDCl 3): d 9.70 (br s, 1 H), 7.69 (t, J = 0.8 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.24 (dd, J = 8.6, 1.8 Hz, 1 H), 6.76 (dd, J = 2.0, 1.0 Hz, H), 3.98 (br m, 4H), 2.54 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H) .
EXAMPLE 43 K¡ = 0.055 μ?
(7-Bromo-1 H-indol-2-yl) - (4-meth yl-piperazin-1-iQ-methanone
1 H NMR (400 MHz, CDCl 3): d 9.06 (br s, 1 H), 7.51 (dt, J = 0.8, 8.1 Hz, 1 H), 7.36 (dd, J = 7.7, 0.8 Hz, 1 H), 6.96 (t, J = 7.8 Hz, 1 H), 6.76 (d, J = 2.3 Hz, 1 H), 3.87 (br m, 4H), 2.43 (t, J = 5.1 Hz, 4H), 2.28 (s, 3H) ). MS: exact mass calculated for Ci4Hi6BrN30, 321.05; m / z found, 322.1 [M + H] +.
The title compound in the following example (44) was prepared according to the general procedure of scheme 3.
EXAMPLE 44 K¡ = 0.095 μ
(5-bromo-benzofuran-2-yl) - (4-methyl-piperazin-1-yl) -metanone
5-Bromo-benzofuran-2-carboxylic acid (0.346 g) in THF (7 ml) was treated with carbonyldiimidazole (0.214 g) and stirred at room temperature for 2 hours after which methyl piperazine (0.129 g) was added. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with a saturated solution of sodium bicarbonate, after which the organic portion was separated, dried over sodium sulfate and filtered. The solvent was evaporated, and the residue was purified by chromatography on silica gel (5% 2M ammonia in methanol / dichloromethane) to give the title compound (0.222g). 1 H NMR (400 MHz, CDCl 3: d 7.75 (d, J = 1.9 Hz, H), 7.45 (dd, J = 8.8, 1.9 Hz, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 3.83 (br s, 4H), 2.48 (5, J = 4.8 Hz, 4H), 2.33 (s, 3H).
1JC NMR (400 MHz, CDCl 3) d 159.4, 153.4, 150.3, 129.6, 129.0, 124.9, 116.8, 113.5, 1 1.3, 55.3, 54.9, 46.1, 42.9.
EXAMPLE 45 K = 10, um
H2) sCH3 (4-hexyl-piperazin-1 H-indol-2-yl) -metanone
Indole-2-carboxylic acid (5.2 g) in THF (200 ml) was treated with carbonyldiimidazole (4.8 g) and stirred at room temperature for 10 minutes, after which 4-methyl-piperazine-3-methylbutyl ester was added. 1-carboxylic acid (5.0 g). The mixture was stirred at room temperature for 72 hours and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic portion was separated, dried over sodium sulfate and filtered, and the solvent was evaporated to give a solid. Recrystallization from hot ethanol gave 4- (1 H-indole-2-carbonyl) -piperazine-1-carboxylic acid terbutyl ester (4.2 g). 4- (1 H -indole-2-carbonyl) -piperazine-1-carboxylic acid terbutyl ester (0.165 g) in dichloromethane (10 mL) was treated with trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour . The solvent was removed under reduced pressure to give a trifluoroacetate salt of (1 H -indol-2-yl) -piperazin-1-yl-methanone. (1 H NMR (400 MHz, CDCl 3): d 7.63 (d, J = 8.07 Hz, 1 H), 7.44 (dd, J = 8.3, 0.8 Hz, 1 H), 7.24 (m, 1 H), 7.08 (m , 1 H), 6.91 (s, 1 H), 4.12 (t, J = 5.0 Hz, 4H), 3.35 (t, J = 5.3 Hz, 4H)). This intermediate was dissolved in acetone (5 ml), treated with potassium carbonate (0.22 g), iodohexane (0.106 g) and heated at 50 ° C for 10 hours. Evaporation of the solvent under reduced pressure gave the crude product which was purified by preparative thin layer chromatography eluting with 10% methanol / dichloromethane to give the title compound (0.06 g). H NMR (400 MHz, CD3OD): d 7.60 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.21 (ddd, J = 8.1, 7.1, 1.1 Hz, 1 H), 7.16-7.04 (m, 1 H), 6.81 (s, 1H), 3.89 (br s, 4H), 2.56 (t, J = 5.0 Hz, 4H), 2.43-2.40 (m, 2H), 1.58 -1.52 (m, 2H), 1.34 (br s, 6H), 0.94-0.90 (m, 3H). The title compounds of the following examples (46-47) were prepared according to the general procedure of scheme 5, as indicated for example 74.
EXAMPLE 46 = 10 μ?
r4- (2-Cyclohexyl-ethyl) -piperazine-1-in- (1H-indol-2-n-methanone EXAMPLE 47 Ki = 10 μ? (1 H-lndol-2-yl) - r4- (4-methyl-pentyl) -piperazin-1-in-methanone
EXAMPLE 48 K¡ = 3 μ?
(3-Bromo-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
(1 H-indol-2-yl) - (4-meth yl-piperazin-1-yl) -methanone (example 4, 0.222 g) in acetic acid (1 ml) at room temperature was treated with bromine (0.05 ml) and stirred for 7 hours. The reaction mixture was poured into water and adjusted to a basic pH by the addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane, gave the title compound (0.154 g).
EXAMPLE 49 Kj = 3 μ?
(3,5-dibrorno-1H-lndol-2-yl) - 4-rnetyl-piperazin-1-yl) -metanone
(1 H -indol-2-yl) - (4-methyl-p-piperazin-1-yl) -methanone (example 4, 0.222 g) in acetic acid (1 ml) at room temperature was treated with bromine (0.10 ml). ) and stirred for 7 hours. The reaction mixture was poured into water and adjusted to a basic pH by the addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane, gave the title compound (0.123 g).
EXAMPLE 50 K¡ = 9 μ?
(4-methyl-piperazin-1-yl) - (3.5.7-tri- bromo-1 H-indol-2-yl) -metanone
(1 H -indole-2-yl) - (4-methyl-p-piperazin-1-yl) -methanone (example 4.222 g) in acetic acid (1 ml) at room temperature was treated with bromine (0.15 ml) and stirred for 7 hours. The reaction mixture was emptied into water was adjusted to a basic pH by the addition of sodium hydroxide 1. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane, gave the title compound (0.038 g).
EXAMPLE 51 Kj = 7 μ?
2- (4-methyl-piperazin-1 -carboniQ-1 H -indole-3-carbaldehyde
(H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone (example 4, 0.206 g) in DMF (1.5 ml) at 0 ° C was treated with phosphorus oxychloride ( 0.1 mi) for 10 minutes. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into water and adjusted to neutral pH by the addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give the crude product. Purification by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane gave the title compound (0.108 g).
EXAMPLE 52? = 10 μ?
(3-hydroxymethyl-1 H-indol-2-yl) - (4-methyl-p-piperazin-1-yl) -metanone
2- (4-methy1-piperazin-1 -carbonyl) -1H-indole-3-carbalde (Example 51, 0.094 g) in ethyl acetate (1.5 ml) was treated with sodium borohydride. (0.024 g) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was treated with a saturated solution of sodium bicarbonate and extracted with dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane, to give the title compound (0.042 g).
EXAMPLE 53 K¡ = 9 μ?
(4-methyl-piperazin-1-yl) - (3-pyrrolidin-1-ylmethi-1 H-indol-2-iQ-methanone)
(1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone (example 4, 0.231 g) in acetic acid (1.5 ml) at room temperature was treated with paraformaldehyde (0.4 g) and pyrrolidine (0.16 ml). The reaction mixture was heated at 60 ° C for 6 hours, then it was poured into water and the solution was adjusted to basic pH by the addition of sodium hydroxide 1. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane gave the title compound (0.1 g).
EXAMPLE 54 K¡ = 0.378 μ?
(3-chloro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
(1H-indol-2-yl) - (4-methy1-piperazin-1-yl) -methanone (Example 4, 0.5 g) in dichloromethane (3 ml) at room temperature was treated with N-chlorosuccinimide (0.301 g) and stirred for 6 hours. The reaction mixture was diluted with ether, washed with water, saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane, gave the title compound (0.36 g). H NMR (400 MHz, CDCl 3): d 2.36 (3 H), 2.52 (4 H), 3.79 (4 H), 7.21 (1 H), 7.31 (1 H), 7.38 (1 H), 7.64 (1 H), 9.05 (1 HOUR).
EXAMPLE 55 Kj = 7.0 μ?
(3,5-Dichloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
(5-Chloro-1 H-indol-2-yl) - (4-methyl-p-piperazin-1-yl) -methanone (Example 1, 0.23 g) in dichloromethane (3 ml) at room temperature was treated with N -chlorosuccinimide (0.123 g) and stirred for 18 hr. The reaction mixture was diluted with ether, washed with water, saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane, gave the title compound (0.13 g). 1 H NMR (400 Hz, CDCl 3): d 2.36 (3 H), 2.53 (4 H), 3.79 (4 H), 7.22 (1 H), 7.29 (1 H), 7.58 (1 H), 10.39 (1 H).
EXAMPLE 56 Kj = 0.238 μ?
(5-Bromo-3-chloro-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
(5-Bromo-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone (example 3, 0.27 g) in dichloromethane (3 ml) at room temperature was treated with N-chlorosuccinimide (0.103 g) and stirred for 18 hr. The reaction mixture was diluted with ether, washed with water, saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography on silica gel, eluting with 1-8% methanol / dichloromethane, gave the title compound (0.16 g). H NMR (400 MHz, CDCl 3): d 2.35 (3 H), 2.52 (4 H), 3.78 (4 H), 7.23 (1 H), 7.35 (1 H), 7.74 (1 H), 9.84 (1 H).
EXAMPLE 57 K¡ = 9 μ?
(3-D-methylaminomethyl-1H-indol-2-ilM4- ^
The title compound was prepared from (1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone (Example 4) according to the general procedure of Example 53 (See: J Am. Chem. Soc, 71: 3541, 1949). H NMR (400 MHz, CDCl 3: d 9.39 (br, 1 H), 7.78 (m, 1 H), 7.34 (m, 1 H), 7.21 (m, 1 H), 7.11 (m, 1 H), 5.28 (s, 2H), 3.69 (br, 4H), 2.40 (br, 4H), 2.29 (s, 3H), 2.24 (s, 6H)). EM (electroaspersion): exact mass calculated for C17H24N40,
300. twenty; m / z found, 301.1 [M + H] +.
EXAMPLE 58 K¡ = 0.132 μ?
(1 H-indol-2-in- (4-methyl-piperazin-1-yl) -methanethione
(1 H-lndol-2-yl) - (4-methy1-piperazin-1-yl) -methanone (Example 4, 0.123 g) in THF (1 mL) was treated with Lawesson's reagent (0.243 g) ) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography to give the title compound (0.02 g). H NMR (400 MHz, CDCl 3): d 9.21 (br s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 7.3 Hz, 1 H), 7.12 (m, 1 H), 6.60 (s, 1 H), 4.39 (br s, 4 H), 3.85 (br s, 4 H), 2.63 (s, 3 H). The title compounds of the following examples (59 and 60) were prepared according to the general procedure of scheme 1.
EXAMPLE 59 K = 46 nM
(4-Methyl-piperazin-1-yl - (5-nitro-1H-indol-2-yl) -metanone
A mixture of 5-nitroindole-2-carboxylic acid (4.38 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 4.89 g) in dichloromethane (150 ml) was treated with N-methylpiperazine (2.83 ml). ) and stirred at room temperature for 16 hr. The reaction mixture was poured into dichloromethane (200 ml), washed with water, saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-10% 2M ammonia in methanol / dichloromethane) to give the title compound (1.8 g). 1 H NMR (400 MHz, CDCl 3): d 10.97 (br s, 1 H), 8.58 (d, J = 2.15 Hz, 1 H), 8.11 (dd, J = 2.15, 7.04 Hz, 1 H), 7.44 (d , J = 9.00 Hz, 1H), 6.89 (s, 1 H), 3.95 (br m, 4H), 2.52 (t, J = 4.89 Hz, 4H), 2.34 (s, 3H). MS: exact mass calculated for CUH16N4O3, 288.12; m / z found, 289.1 [M + H] +.
EXAMPLE 60 Ki = 6.6 nM
(7-methyl-1 H-indol-2-in- (4-methyl-pipera-2-yl) -metanone
A mixture of 7-methylindole-2-carboxylic acid (1.79 g, 10 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC)2.88 g, 15 mmol) in CH2Cl2 (100 mL) was treated with N-methylpiperazine (2.22 mL, 20 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), washed with water (25 ml X2) and then brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. This product was purified by chromatography on silica gel (5-10% methanol / dichloromethane) to give the title compound as a white solid (2.5 g, 97.3%). 1H RN (400 MHz, CDCl 3): d 1 1.07 (br s, 1 H), 7.43 (d, J = 7.04 Hz, 1 H), 7.00-6.92 (m, 2H), 6.71 (d, J = 1.96 Hz , 1 H), 3.86 (br s, 4H), 2.37 (s, 3H), 2.35-2.28 (m, 4H), 2.19 (s, 3H). EM (electroaspersion): exact mass calculated for Ci5HigN30,
257. fifteen; m / z found, 258.2 [M + H] +.
EXAMPLE 61 K = 19 nM
(5-amino-1 H -indo-2-yl) - (4-methyl-piperazin-1-yl) -metanone
The product of Example 59, (4-methyl-piperazin-1-yl) - (5-nitro-1 H-indol-2-yl) -methanone (1.8 g) was dissolved in CH 3 OH (50 mL). At room temperature, ammonium formate (3.94 g) was added, followed by 10% palladium on carbon (0.66 g). The reaction mixture was heated to reflux for 40 minutes, cooled and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by chromatography on silica gel (3- 0% 2M ammonia in methanol / dichloromethane) to give the title compound (1.60 g). H NMR (400 MHz, CDCl 3): d 10.46 (br s, 1 H), 7.12 (d, J = 8.80 Hz, 1 H), 6.81 (d, J = 2.15 Hz, 1H), 6.64 (dd, J = 2. 5, 6.46 Hz, 1 H), 6.54 (d, J = 1.37 Hz, 1 H), 3.88 (br m, 4H), 3.70 (br s, 2H), 2.40 (t, J = 4.70 Hz, 4H ), 2.25 (s, 3H). EM (electroaspersion): exact mass calculated for Ci4Hi8N 0,
258. fifteen; m / z found, 259.1 [M + H] +.
EXAMPLE 62 K = 7 nM
(7-amino-1 H-indol-2-8l) - (4-methyl-p-piperazin-1-iQ-methanone
The product of Example 8, (4-methyl-piperazin-1-yl) - (7-nitro-1 H -indole-2-yl) -methanone (6.4 g, 22.2 mmol), was dissolved in CH3OH (110 mL). ). At room temperature, ammonium formate (14.0 g, 222 mmol) was added, followed by 10% palladium on carbon (2.4 g, 2.22 mmol). The reaction mixture was refluxed for 40 minutes, cooled and then filtered through a pad of celite. The filtrate was concentrated and the residue was purified by chromatography on silica gel (3-10% 2M ammonia in methanol / dichloromethane) to give the title compound (4.4 g, 76.7%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 CD 3 OD): d 7.08 (d, J = 7.83 Hz, 1 H), 6.94 (t, J = 7.83 Hz, 1 H), 6.73 (s, 1 H), 6.58 (d, J = 7.63 Hz, 1 H), 4.12 (s, 2H), 3.92 (br s, 4H), 2.51 (br s, 4H), 2.34 (s, 3H). E (electroaspersion): exact mass calculated for Ci Hi8N40,
258. fifteen; m / z found, 259.1 [M + H] +.
The title compounds of the following examples (63 to 66) were prepared according to the general procedure of scheme 1.
EXAMPLE 63 Ki = 32.5 nM
(6-hydroxy-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
Ethyl 6-methoxy-1H-indole-2-carboxylic acid ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 ml) followed by water (30 ml) and stirred at room temperature for 16 hours. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give 6-methoxy-1 H-indole-2-carboxylic acid (4.60 g). This material (4.64 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.60 g) in dichloromethane (200 ml) was treated with N-methylpiperazine (3.23 ml) and stirred at room temperature for 16 hours. The reaction mixture was poured into dichloromethane (200 ml), washed with water, saturated sodium bicarbonate solution and brine, then over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel 0-10% 2M ammonia in methanol / dichloromethane) to give (6-methoxy-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) ) -metanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 ml). At room temperature, 1 M boron tribromide (1.5 ml) was added dropwise. The reaction mixture was heated to reflux overnight and then cooled, quenched with a saturated solution of sodium bicarbonate and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (0-10% 2M ammonia in methanol / dichloromethane) to give the title compound (0.12 g). 1 H NMR (400 MHz, CDCl 3 / CD 3 OD): d 7.22 (d, J = 8.41 Hz, 1 H), 6.62 (d, J = 2.15 Hz, 1 H), 6.5-6.47 (m, 2 H), 3.69 (br s, 4H), 2.30 (t, J = 5.09 Hz, 4H), 2.13 (s, 3H). EM (electroaspersion): exact mass calculated for C 14 H 17 N 3 O 2, 259.13; m / z found, 260.1 [M + H] +.
EXAMPLE 64 K¡ = 41 nM
(5-chloro-1 H-indol-2-yl) - (3-methyl-piperazin-1-yl) -metanone
A mixture of 5-chloroindole-2-carboxylic acid (0.196 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.288 g) in dichloromethane (10 ml) was treated with 2-methyl-piperazine (0.15 g) and it was stirred at room temperature for 16 hours. The reaction mixture was poured into dichloromethane (50 ml), washed with water, saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0.10% methanol / dichloromethane) to give the title compound (0.229 g). H NMR (400 MHz, CDCl 3): d 10.99 (br s, 1 H), 7.55 (d, J = 1.76 Hz, 1 H), 7.33 (d, J = 8.80 Hz, 1 H), 7.14 (dd, J = 1.96, 6.65 Hz, 1H), 6.64 (br s, 1 H), 4.55 (br s, 2 H), 3.23-2.61 (m, 5 H), 1.76 (br s, 1 H), 1.08 (d, J = 5.87 Hz, 1 H). EM (electroaspersion): exact mass calculated for m / z found, 278.1 [M + H] +.
EXAMPLE 65 K¡ = 36 n
(5-chloro-1 H -indol-2-yl) - (3-methyl-piperazin-1-yl) -metanone
1 H NMR (400 MHz, CDCl 3: d 10.99 (br s, 1 H), 7.55 (d, J = 1.76 Hz, 1 H), 7.33 (d, J = 8.80 Hz, 1 H), 7.14 (dd, J = 1.96, 6.65 Hz, 1 H), 6.63 (br s, 1 H), 4.55 (br s, 2 H), 3.23-2.61 (m, 5 H), 1.76 (br s, 1 H), 1.08 (d, J = 5.87 Hz,
1 HOUR). (electroaspersion): exact mass calculated for
C14H16CIN30, 277.10; m / z found, 278.1 [M + H] +.
EXAMPLE 66 K = 34 nM
(5-Chloro-1 H -indo-2-yl) - (3-methyl-piperazin-1-yl) -metanone
1 H NMR (400 MHz, CDCl 3): d 10.99 (br s, H), 7.55 (d, J = 1.76 Hz, 1 H), 7.33 (d, J = 8.80 Hz, 1 H), 7.14 (dd, J = 1.96, 6.65 Hz, 1 H), 6.63 (br s, 1 H), 4.55 (br s, 2 H), 3.23-2.61 (m, 5 H), 1.76 (br s, 1 H), 1.08 (d, J = 5.87 Hz, 1H). EM (electroaspersion): exact mass calculated for m / z found, 278.1 [M + Hf.
EXAMPLE 67 K = 27 nM
f5-Chloro-1H-indol-2-in-f3,4-dimethyl-piperazin-1-yl) -metanone
The product of example 64 (5-chloro-1 H-indol-2-yl) - (3-methyl-piperazin-1-yl-methanone (0.19 g) was dissolved in dichloromethane (10 ml). was added to formaidehyde (0.031 g), followed by acetic acid (1 drop) .The reaction mixture was stirred at room temperature for 5 hours.Sodium triacetoxyborohydride (0.318 g) was added.The reaction mixture was stirred at room temperature for 16 hours and it was drained in dichloromethane (20 ml), washed with water, saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by chromatography on silica gel (0-10% methanol / dichloromethane) to give the title compound (0.22 g) H NMR (400 Hz, CDCl 3): d 10:69 (br s, 1 H), 7.56 (d, J = 1.76 Hz, 1H), 7.33 (d, J = 8.80 Hz, 1 H), 7.16 (dd, J = 1.96, 5.66 (d, J = 1.57 Hz, 1 H), 4.63-4.36 (m, 2H) , 3.63-2.67 (m, 3H), 2.30 (s, 3H), 2.30-2.20 (m, 1 H ), 2.18-2.09 (m, 1 H), 1.12 (d, J = 5.87 Hz, 1H). EM (electroaspersion): exact mass calculated for m / z found, 292.1 [M + H] +. The title compound of the following example (68) was prepared according to the general procedure of scheme 5.
EXAMPLE 68 K = 43 nM
(7-amino-1 H-indol-2-yl) -piperazin-1-yl-methanone
A mixture of 7-nitroindol-2-carboxylic acid (4.38 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.89 g) in dichloromethane (50 ml) was treated with piperazinyl-tert-butyl ester. carboxylic acid (1.63 g) and stirred at room temperature for 16 hours. The reaction mixture was poured into dichloromethane (20 ml), washed with water, saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-5% methanol / dichloromethane) to give 4- (7-nitro-1 H-indole-2-carbonyl) -piperazine-1-carboxylic acid terbutyl ester (2.17 g). This material (1.69 g) was dissolved in CH3OH (50 ml). At room temperature, ammonium formate (2.85 g) was added followed by 10% palladium on carbon (0.47 g). The reaction mixture was heated to reflux for 40 minutes, cooled and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by chromatography on silica gel (0-10% methanol / dichloromethane) to give 4- (7-amino-1 H-indole-2-carbonyl) -piperazine- terbutyl ester. 1-carboxylic acid (1.34 g). This material (1.3 g) was treated with 20% trifluoroacetic acid / dichloromethane (50 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give trifluoroacetate salt of (7-amino-1 H -indol-2-yl) -piperazin-1-yl-methanone. The intermediate was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-10% ammonia in methanol / dichloromethane) to give the title compound (0.824 g). 1 H NMR (400 MHz, CDCl 3 OD): d 7.09 (d, J = 7.83 Hz, 1 H), 6.95
(t, J = 7.63 Hz, 1 H), 6.72 (s, 1 H), 6.60 (d, J = 7.63 Hz, 1 H), 4.20 (br s, 4 H), 3.88 (br s, 4 H), 2.94 (t, J = 5.09 Hz, 3H). EM (electroaspersion): exact mass calculated for Ci3H16N40,
244. 13; m / z found, 245.1 [M + H] +. The title compounds of the following examples (69-70) were prepared according to the general procedure of scheme 4.
EXAMPLE 69 K = 47 nM
(7-hydroxy-1H-indol-2-in- (4-methyl-piperazin-1-yl) -methanone
At room temperature, methyl oxalate (13.6 ml) was added to a solution of potassium ethoxide (8.4 g) in anhydrous ethyl ether (200 ml). After 10 minutes, 3-methyl-2-nitroanisole (16.7g) was added and stirred at room temperature for 24 hours. The deep, misty purple potassium salt was filtered off and washed with anhydrous ether until the filtrate remained colorless. This salt was dissolved in aqueous ammonium chloride and the solution was extracted with dichloromethane. The combined organic extracts were washed with salmlue, dried over sodium sulfate and filtered, and the solvent was evaporated. The residue was purified by chromatography on silica gel (5-30% ethyl acetate / hexanes) to give 3- (3-methoxy-2-nitro-phenyl) -2-oxo-propionic acid ethyl ester ( 14.0 g). This material (14.0 g) was dissolved in ethanol (200 ml) containing 5% by weight of palladium on activated carbon (1.4 g) and placed on a Parr hydrogenator at a pressure of 4.22 kg / cm2 of H2. After 2 hours, the mixture was filtered through celite and concentrated to give a clear liquid. The liquid was purified by chromatography on silica gel (5% -30% EtOAc / hexanes) to obtain (7-methoxy-1H-indol-2-yl) - (4-methyl-6-methoxy) ethyl ester. -1 H -indole-2-carboxylic acid (11.7 g) This ethyl ester (4.0 g) was treated with lithium hydroxide (1.75 g) in THF (100 ml) followed by water (30 ml) and stirred at room temperature The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate.The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give acid. 6-methoxy-1H-indole-2-carboxylic acid (3.50 g) This material (3.50 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.26 g) in dichloromethane (100 ml) was treated with N-methylpiperazine (3-05 mL) and stirred at room temperature for 16 hours The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium bicarbonate solution After brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-10% methanol / dichloromethane) to give (7-methoxy-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone (4.50 g). This material (3.5 g) was dissolved in dichloromethane (85 ml). At room temperature, 1 M boron tribromide (2.42 ml) was added dropwise. The reaction mixture was refluxed for 2 hours, cooled and then quenched with saturated sodium bicarbonate solution. The suspension was filtered. The filtrate was washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate and filtered, and the solvent was evaporated. The residue was purified by chromatography on silica gel (0-10% methanol / dichloromethane) to give the title compound (1.95 g) - 1 H NMR (400 MHz, CDCl 3 / CD 3 OD): d 7.52 (s, 1?) , 7.16 (dd, J = 0.78, 7.24 Hz, 1 H), 6.96 (t, J = 7.63 Hz, 1 H), 6.77 (s, 1 H), 6.70 (dd, J = 0.98, 6.65 Hz, 1 H ), 3.93 (br s, 4H), 2.55 (t, J = 5.09 Hz, 4H), 2.38 (s, 3H). EM (electroaspersion): exact mass calculated for Ci4Hi7N302)
259. 13; m / z found, 260.1 [M + H] +.
(5,7-dimethyl-H-dimol-2-yl) - (4-methyl-piperazin-1-n-methanone)
1 H NMR (400 MHz, CDCl 3): d 10.68 (br s, 1 H), 7.20 (s, 1 H), 6.80 (s, 1 H), 6.65 (d, J = 2.15 Hz, 1 H), 3.91 ( br s, 4H), 2.39 (t, J = 4.50 Hz, 4H), 2.35 (s, 6H), 2.26 (s, 3H). EM (electroaspersion): exact mass calculated for C-16H21N3O,
271. 17; m / z found, 272.1 [M + H] +.
EXAMPLE 71 K¡ = 19 nM
(5-hydroxy-1 H -indol-2-yl-4-methyl-piperazin-1-yl) -metanone
A mixture of the product of Example 5 (5-benzylloxy-1 H-indol-2-yl) - (4-methyl-pyrrazin-1-yl) -methanone (0.2 g) in a mixture of ethanol (3 mi) and ethyl acetate (5 ml) was treated with 10% palladium on carbon (approximately 0.025 g) and hydrogenated at atmospheric pressure for 2 hours. The reaction mixture was filtered through a pad of celite and the residue was washed with methanol. The solvent in the combined filtrates was removed under reduced pressure and the residue was purified by chromatography on silica gel (3-10% 2M ammonia in methanol / dichloromethane) to give the title compound (0.034 g, 23%). 1 H NMR (400 MHz, CD 3 OD): d 7.20 (d, J = 8.0 Hz, 1H), 6.90 (m, 1 H), 6.75 (dd, J = 4, 8 Hz, 1 H), 6.54 (m, 1 H), 3.80 (br m, 4H), 2.44 (m, 4H), 2.27 (s, 3H). EM (electroaspersion): exact mass calculated for C14H17N3O2,
259. 13; m / z found, 260.0 [M + H] +.
EXAMPLE 72 K = 1 1 nM
(4-5-dichloro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
The title compound was prepared according to the general procedure of scheme 2. A mixture of 3,4-dichlorophenylhydrazine (5.0 g) in benzene (50 ml) was treated sequentially with ethyl pyruvate (2.6 ml) and p-toluenesulfonic acid. (trace amount). The mixture was heated to reflux temperature (Dean and Stark conditions) for 5 hours, then cooled to room temperature to give a solution of 2 - [(3,4-dichloro-phenyl) -hydrazone] ethyl ester. -propionic Separately, a solution of p-toluenesulfonic acid (15 g) in benzene (150 ml) was heated at reflux temperature (Dean and Stark conditions) for 2 hours and then treated with the hydrazone solution. After 3 hours, the reaction mixture was cooled and treated with a saturated solution of sodium bicarbonate and diethyl ether. The organic fraction was separated, washed with a saturated solution of sodium bicarbonate and then brine, dried over magnesium sulfate and filtered, and the solvent was evaporated to give an orange solid. The solid was purified by chromatography on silica gel (5-75% ethyl acetate / hexane) to give 4,5-dichloro-1 H-indole-2-carboxylic acid ethyl ester (0.5 g, 8%) and ethyl ester of 5,6-dichloro-1H-indole-2-carboxylic acid (0.297 g, 5%). These materials were used separately without further purification. Ethyl ester of 4,5-dichloro-1H-indole-2-carboxylic acid (0.5 g) was treated with 1 M lithium hydroxide in ethanol (3 mL) and heated in a water bath for 2 hours. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and filtered, and the solvent was evaporated to give 4,5-dichloro-1H-indole-2-carboxylic acid (0.27 g, 60%). This material was treated with ethyl-3- (3'-dimethylaminopropyl-carbodiimide hydrochloride (0.5 g), HOBT (0.4 g) and N, N-diisopropylethylamine (1 ml) in DMF (2 ml) and dichloromethane (2 ml). It was treated with N-methylpiperazine (0.2 ml), stirred at room temperature for 18 hours and diluted with water, the organic portion was separated, washed with brine, dried over sodium sulfate and filtered. reduced pressure and the residue was purified by chromatography on silica gel (3-8% 2M ammonia in methanol / dichloromethane) to give the title compound (0.15 g, 40%). 1 H NMR (400 MHz, CDCl 3): d 10.2 (br.s, 1H), 7.25 - 7.16 (m, 2H), 6.75 (d, J = 2Hz, 1 H), 3.92 (br.m, 4H), 2.47 (m, 4H), 2.30 (s) , 3H) EM (electroaspersion): exact mass calculated for m / z found, 312.0 [M + H] +.
EXAMPLE 73 K¡ = 259 nM
(5,6-Dichloro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone
Using the procedure of the previous example (72), the title compound was prepared from 5,6-dichloro-1 H-indole-2-carboxylic acid ethyl ester. 1 H NMR (400 MHz, CDCl 3): d 9.9 (br.s, 1 H), 7.97 (s, 1 H), 7.79 (m, 1 H), 6.94 (m, 1 H), 4.20 (br.m, 4 H) , 2.77 (m, 4H), 2.26 (s, 3H). EM (electroaspersion): exact mass calculated for m / z found, 312.0 [M + H] +. The title compound of the following example (74) was prepared according to the general procedure of scheme 5.
EXAMPLE 74 K¡ = 0.025 μ?
(5-chloro-1H-indoi-2-i Vf4- (2-h.). Droxy-ethyl) -piperazine-1-UVrnetanone
A. 4- (5-Chloro-1 H -indole-2-carbonylo-piperazine-1-carboxylic acid terbutyl ester A mixture of 5-chloroindole-2-carboxylic acid (10 g), tert-butyl 1-piperazinecarboxylate (10.5) g) and 4-dimethylaminopyridine (6.3 g) in CH 2 Cl 2 (200 ml) was treated with a catalytic amount of HOBT (0.2 g) The resulting mixture was cooled to 0 ° C, and EDCI (10.8 g) was added. it was slowly warmed then to room temperature and stirred at 24 hours, then concentrated under reduced pressure, water was added to the resulting residue, the product was purified and washed with water (2 x 50 mL) and Et2O (30 mL). The resulting solid was dried under reduced pressure to give (18.2 g). (Electroaspersion): calculated exact mass Cish ClNaOs, 363.13; m / z found, 362.3 [M + H] +.
B. (5-Chloro-1H-indol-2-yl) -piperazin-1-yl-methanone The product of step A (11 g) was suspended in CH2Cl2 (75 ml), and TFA (75 mL) was added dropwise. my). The resulting solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and the resulting residue was dissolved in CH2Cl2 (100 mL). Saturated aqueous NaHCO3 (100 mL) was slowly added with stirring. After 20 minutes the organic layer was separated, washed with water (10 mL) and then brine (30 mL), and dried over Na2SO4. The organic layer was then concentrated under reduced pressure and purified by chromatography on silica gel (0-35% methanol / dichloromethane) to give the title compound (7.6 g) -MS (electroaspersion): exact mass calculated for C 13 H 24 CIN 30, 263.08; m / z found, 264.1 [M + H] +.
C. (5-chloro-1 H-indol-2-in-f4- (2-hydroxy-ethyl) -piperazin-1-methyl-methanone The product from step B (1.0 g) was dissolved in CH3CN (10 ml) and treated with 2-bromoethanol (0.5 g) and then K2C03 (0.8 g) .The resulting mixture was heated at 60 ° C overnight.The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-10% methanol / dichloromethane) to give the title compound (0.5 g).
H NMR (400 MHz, CDCl 3): d 10.09 (br s, 1 H), 7.61 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 7.23 (dd, J = 2.0, 8.8 Hz, 1 H), 6.69 (d, J = 0.8 Hz, H), 3.95 (br m, 3H), 3.72-3.69 (m, 2H), 2.67-2.64 (m, 4H), 2.52 ( br s, 3H). EM (electroaspersion): exact mass calculated for
C15H18CIN302, 307.78; found miz, 308.1 [M + H] +.
EXAMPLE 75 K¡ = 0.145 μ?
r5- (3-methoxy-phenol) -1H-indol-2-in- (4-methyl-piperazin-1-yl-methanone
A suspension of (5-bromo-1 H -indol-2-yl) - (4-methyl-p-piperazin-1-yl) -methanone (example 3, 0.057 g) in dry toluene (0.5 ml) was treated with pd (OH) 2 (0.001 g) under N2 atmosphere. The resulting mixture was then treated with 3-methoxyphenylboronic acid (0.057 g) and then K3PO4 (0.12 g), and heated at 95 ° C for 24 hours. The reaction mixture was cooled to room temperature and diluted with water (2 ml) and toluene (10 ml). The organic layer was separated and washed with brine (2 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-12% methanol / dichloromethane) to give the title compound (0.005 g). HRN (400 Hz, CDCI3): d 9.96 (br s, 1 H), 7.53 (d, J = 1.6 Hz, 1 H), 7.51 (d, J = 1.6 Hz, 1 H), 7.35 (t, J = 7.9 Hz, 1 H), 7.23 (s, 1 H), 7.21 (s, 1H), 7.17 (m, 1H), 6.87 (d, J = 2.2, 8.1 Hz, 1 H), 6.82 (d, J = 1.8 Hz, 1 H), 3.99 (br s, 4 H), 3.86 (s, 3 H), 2.52 (t, J = 4.9 Hz, 4 H), 2.35 (s, 3 H). EM (electroaspersion): exact mass calculated for C21H23N3O2,
349. 18; m / z found, 350.2 [M + H] +. The title compound of the following example (76) was prepared according to the general procedure of Example 75.
EXAMPLE 76 K¡ = 0.327 μ?
(4-methyl-piperazin-1 -iQ- (5-p-tolyl-1 H-indol-2-iQ-methanone
1 H NMR (400 MHz, CDCl 3): d 9.24 (br s, 1 H), 7.81 (m, 1 H), 7.54- .46 (m, 5 H), 7.26 (d, J = 7.8 Hz, 1 H), 6.82 (dd, J = 0.7, 2.1 Hz, 1 H), 3.97 (br s, 4H), 2.52 (t, J = 5.1, 4H) 2.40 (s, 3H), 2.36 (s, 3H). MS (electroaspersion): exact mass calculated for C21H23N3O, 333.18; m / z found, 334.2 [M + H] +.
F. Biological examples
EXAMPLE 1 Binding assays on recombinant H4 human histamine receptor
SK-N-MC cells p COS7 cells were transiently transfected with pH4R and grown in tissue culture boxes of 150 cm2. The cells were washed with saline, scraped with a cell scraper and collected by centrifugation (1000 rpm, 5 min). The cell membranes were prepared by homogenizing the cell pellet in 20 mM Tris-HCl with a polytron tissue homogenizer for 10 seconds at high speed. The homogenate was centrifuged at 1000 rpm for 5 minutes at 4 ° C. The supernatant was then collected and centrifuged at 20,000 x g for 25 minutes at 4 ° C. The final pellet was resuspended in 50 mM Tris-HCl. The cell membranes were incubated with 3H-histamine (5 nM-70 nM) in the presence or absence of excess histamine (10000 nM). Incubation occurred at room temperature for 45 minutes. Membranes were harvested by rapid filtration on Whatman GF / C filters and washed 4 times with 50 mM ice-cold Tris HCI. The filters were then dried, mixed with scintillant and counted for radioactivity. SK-N-MC or COS7 cells expressing human histamine H4 receptor were used to measure the binding affinity of other compounds and their ability to displace the 3H ligand binding by incubating the above-described reaction in the presence of various concentrations of inhibitor or compound that has to be tested. For competition binding studies that used 3 H-histamine, the K i values were calculated based on the experimentally determined K D value of 5 nM and a ligand concentration of 5 nM according to Cheng and Prusoff where: K = (Cl50) / (1 + ([L] / (KD)).
EXAMPLE 2 Inhibition of zymosan-induced peritonitis in mice by histamine H4 receptor antagonists
This example demonstrates the discovery that histamine H 4 receptor antagonists can block peritonitis induced by zymosan, which is the insoluble polysaccharide component on the cell wall of Saccharomyces cerevisiae. This is commonly used to induce peritonitis in mice and appears to act in a mast cell-dependent manner.
Materials and methods
Animals Male non-inbred Swiss albino mice were purchased from Bantin and Kingman (TO strain, Hull, Humberside) and kept on a standard mouse diet of mice feed with tap water and ad Ubitum and a light / dark cycle of 12:00 hours All animals were housed for at least 3 days before experimentation to allow the body weight to reach -30 g on the day of the experiment. For this particular experiment, the body weight was 30.5 ± 0.3 g (n =. · 32). The animals were briefly anesthetized (30-60 sec) with halothane for all the subcutaneous and intraperitoneal treatments described below.
Treatment and experimental design of the drugs The drugs were stored at room temperature, in the dark. On the day of the experiment the drugs were dissolved in sterile PBS as illustrated below, and subjected to generous swirling action. The compound of chemical example 1 was prepared at 10 mg / 5 ml, and injected at 5 ml / kg. Imetit was prepared at 5 mg / ml and injected at 5 ml / kg. Thioperamide was prepared at 5 mg / ml and injected at 5 ml / kg. Time-15 minutes: PBS compounds administered subcutaneously at the doses reported.
Time 0: at time 0, the mice received 1 mg of zymosan A (Sigma) intraperitoneally. Time +2 hr: compounds or PBS administered subcutaneously at the doses reported. Time +4: the peritoneal cavities were washed 4 hours later with 3 ml of PBS containing 3 mM EDTA, and the number of leukocytes that migrated was determined, taking an aliquot (100 μl) of the washing fluid and diluting 1: 10 in Turk's solution (0.01% violet crystal in 3% acetic acid). The samples were then subjected to swirling action and 10 μ? of the stained cell solution were placed in a Neubauer hemocytometer. Differential cell counts were made using an optical microscope (Olympus B061). In view of the chromatic characteristics and its nucleus and cytoplasmic appearance, polymorphonuclear leukocytes (PMN) could be easily identified; > 95% neutrophils). The experimental groups are described below: PBS + zymosan, n = 8 Compound of example 1 + zymosan, n = 8 Imetit + zymosan, n = 8 Thioperamide + zymosan, n = 8
Statistics Data are shown for a single mouse, and are also shown as mean ± SD or standard error (SE) of 8 mice per group. The percent inhibition is also shown. The statistical differences determined by Anova followed by the post-hoc Bonferroni test.
Results
TABLE 1 Effect of compounds on peritonitis by zvmosan
Treatment n PMN Mean DE EE P value (106 per mouse) (% inhibition)
PBS 1 15.9 17.2 2.4 0.8 (s.c) 2 18.3 3 16.2 4 17.4 5 19.8 6 12.6 7 19.8 8 17.7 Compound 1 1 9.9 6.6 2.7 1.0 0.001
(10 mg / kg; s.c.) 2 3.6 (-62%) 3 9.3 4 3.3 5 8.1 6 5.1 7 6.9 Imetit 1 19.8 17.3 2.6 0.9 n.s.
(5 mg / kg; s.c.) 2 17.1 3 14.1 4 15.3 5 21.3 6 17.7 7 14.1 8 18.6 Tioperamide 1 9.3 9.3 3.4 1.2 0.001
(5 mg / kg; s.c.) 2 16.5 (-46%) 3 7.2 4 10.8 5 5.4 6 9.9 7 6.9 8 8.1
From the data analysis it can be seen that zymosan produced a leukocyte extravasation response that was intense at the 4 hour time point. Treatment with 10 mg / kg of compound 1 significantly reduced the incoming PMN flow (compare the group of PBS with the group of compound 1 in table 1). The degree of inhibition was Imetit > 60% (5 mg / kg) was inactive, while a significant inhibitory effect was achieved by 5 mg / kg of thioperamide.
Conclusion To conclude, this study demonstrates that a histamine H4 receptor antagonist, compound 1, given at a dose of 10 mg / kg, is effective in reducing PMN accumulation in an experimental model of cell recruitment in response to Local application of zymosan in the mouse peritoneal cavity. In addition, thioperamide which is a double H 3 H 4 receptor antagonist is also effective. The double H3 H4 receptor agonist, Imetit, has no effect. This shows that a histamine H4 receptor antagonist can block the inflammation induced by zymosan.
EXAMPLE 3 Inhibition of crystal-induced sodium urate peritonitis in mice by histamine H receptor antagonists
This example demonstrates the discovery for the first time that histamine H 4 receptor antagonists can block peritonitis induced by sodium urate crystals. These crystals are the main cause of the inflammation associated with acute gouty arthritis.
Materials and methods Animals Male non-inbred Swiss albino mice were purchased from Bantin and Kingman (TO strain, Hull, Humberside) and maintained on a standard mouse diet of mice feed with tap water and ad libitum and a light cycle darkness of 12:00 hours. All animals were housed for at least 3 days before experimentation to allow the body weight to reach -30 g on the day of the experiment. For this particular experiment, the body weight was 30 ± 1 (n = 32).
Treatment and experimental drug design Compound 1 was stored at room temperature in the dark. On the day of the experiment, compound 1 was dissolved in saline buffered at its pH with phosphate (PBS) at a concentration of 3 mg / ml.
Within 15 minutes, compound 1 was administered subcutaneously at the dose of 10 mg / kg, while the control group received the vehicle alone (10 ml / kg). Mice received 3 mg of monosodium urate crystals (MSU) given intraperitoneally in time 0. At time +2 hr and at time +4 hr, compound 1 (10 mg / kg) or vehicle (10 ml / kg) was given subcutaneously. Time +6 hr: the peritoneal cavities were washed 6 hours later with 3 ml of PBS containing 3 mM EDTA, and the number of leukocytes that migrated was determined, taking an aliquot (100 μl) of the washing fluid and diluting 1 : 10 in Turk's solution (0.01% violet crystal in 3% acetic acid). The samples were then subjected to swirling action and 10 μ? of the stained cell solution were placed in a Neubauer hemocytometer. Differential cell counts were made using an optical microscope (Olympus B061). In view of the chromatic characteristics and their nucleus and cytoplasmic appearance, polymorphonuclear leukocytes (PMN;> 95% neutrophils) could be easily identified. The experimental groups are described below: Vehicle + MSU crystals n = 8 Compound 1 + MSU crystals n = 8
Statistics The data is shown for individual mice, and also
show as mean ± SE of (n) mice per group. The differences
Statistics were determined by the Student test. A value of P < 0.05 was taken as significant.
Results
TABLE 2 Effect of compound 1 on leukocyte migration induced by MSU as assessed at the 6 hr time point
Treatment n PMN Mean DE EE P value (106 per mouse) (% inhibition)
PBS 1 9.6 8.9 2.2 0.8 (s.c) 2 12.9 3 7.2 4 9.9 5 6.6 6 7.2 7 10.5 8 7.5 Compound 1 1 7.8 6.8 2.1 0.7 0.04
(10 mg / kg; s.c.) 2 4.5 (-24%) 3 3.0 4 7.8 5 8.1 6 9.3 7 6.6 8 7.2
Mice were treated either with PBS (10 ml / kg) or compound 1 (10 mg / kg) at 15 min, +2 hr and +4 hr, and with 3 mg of MSU crystals at time 0. The Incoming flow of PMN into the peritoneal cavity was measured at the 6 hr time point after collection of wash fluids and specific staining as described in the experimental section.
Conclusion As expected, the MSU crystals produced an extravasation of PMN that was intense at the time point of 6 hr. Treatment with specific histamine H4 receptor antagonist, compound 1, significantly reduced PMN migration (Table 2): the degree of inhibition was 24%. To conclude, this study demonstrates that a histamine H4 receptor antagonist is effective in reducing PMN accumulation in an experimental model of cell recruitment in response to local application of MSU crystals in the mouse peritoneal cavity.
EXAMPLE 4 Inhibition of Topic Inflammation Induced by Croton Oil in Mice by Histamine H4 Receptor Antagonists
This example demonstrates the discovery that histamine H4 receptor antagonists can block the inflammation associated with topical application of croton oil.
Materials and methods
Animals Mice derived from male or female ICR weighing 22 ± 1 g were used. The allocation of space for 5 animals was 45 x 23 x 15 cm. The mice were housed in APEC R cages. All animals were kept in a controlled environment of temperature (22 ° C - 24 ° C) and humidity (60% - 80%) with light / dark cycles of 12 hours. Free access to standard laboratory food for mice (LabDiet Rodent Diet, PMI Nutrition International, USA) and tap water was granted.
Chemical substances Acetone (Wako, Japan), croton oil (Sigma, USA), indomethacin (Sigma, USA) and pyrogen-free saline solution (Astar, Taiwan).
Topical inflammation induced by croton oil protocol Groups of 5 male mice derived from ICR weighing 22 ± 1 g were used. Compound 1 (10 mg / kg) and vehicle (0.9% NaCl) as well as the positive control indomethacin (30 mg / kg) were administered subcutaneously to test animals 30 minutes before, and 2 and 4 hours after that croton oil (8% in 20 μ of acetone) was applied topically. The inflammation of the ears was measured by a micrometer of the Dyer model 6 hours after the croton oil as an index of inflammation.
Results
TABLE 3 Effect of Compound 1 on Topical Inflammation Induced by Croton Oil
Treatment n Difference in the mean EE value of P (% thickness of the inhibition) ear (x0.01 mm) PBS 1 12 16.6 1.4 (s.c) 2 17 3 15 4 19 5 20 Compound 1 1 12 12.0 1.2 0.03
(10 mg / kg; s.c.) 2 10 (-28%) 3 13 4 9 5 16 Indomethacin 1 5 10.0 1.3 0.001
(30 mg / kg; s.c.) 2 10 (-40%) 3 12 4 12 5 11
Conclusions
In the ear inflammation test with topical inflammation induced by croton oil, a histamine H4 receptor antagonist, compound 1, at a dose of 10 mg / kg x 3 (s.c.) significantly reduced the
Inflammation with respect to vehicle control. This effect was similar to indomethacin (30 mg / kg x 3). These results show that the histamine H4 receptor antagonist can act as an anti-inflammatory agent.
EXAMPLE 5 Cell type distribution of H4 expression
RNA was prepared from the different cells using a RNeasy kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. RNA samples (5 μg) were made on an RNA gel and then transferred overnight to a nylon marker (Hybond, Amersham Pharmacia Biotech, Piscataway, NJ). The label was prehybridized with an ExpressHyb solution (CLONTECH) for 30 minutes at 68 ° C. The H4 DNA was labeled using the rediprima II kit (Amersham Pharmacia Biotech). The label was hybridized for 2 hours at 68 ° C, followed by a wash step (23 SSC and 0.05% SDS) for 40 minutes at room temperature, and a second washing step (0.13 SSC and 0.1% SDS) for 40 minutes. at 50 ° C. The marker was exposed to an X-ray film at 27 ° C with two intensifying screens during the night.
Conclusion The Northern Blot results indicate that the H4 receptor is expressed on mast cells derived from bone marrow (B MC), peritoneal mast cells and eosinophils. These positive results are consistent with published literature (eg, Oda et al., Nguyen et al., And Morse et al., In the background section). However, the negative results of the Northern Blot experiment, such as the finding of apparently non-measurable levels of H receptor expressed by neutrophils, differ somewhat from the findings of the previous literature. This can be explained by the different methodologies used. Additional research can also clarify these issues.
TABLE 4 Distribution of H¿ expression cell type by Northern Blot
Species Type of cell H4 Human Eosonophils Immature dendritic cells Mature dendritic cells Monocytes CD14 + CD4 + T cells CD8 + cells B Neutrophils Mouse Eosinophilic mice + peritoneal mast cells + BMMC + BM-derived macrophages Peritoneal macrophages CD4 + T cells B cells
Other embodiments The features and advantages of the invention are obvious to one skilled in the art. Based on this description, including the summary, detailed description, background, examples and claims, one skilled in the art will be able to make modifications and adaptations to various conditions and uses. The publications described here are incorporated by reference in their entirety. These other embodiments are also within the scope of the invention.
Claims (1)
- NOVELTY OF THE INVENTION CLAIMS 1. - A compound of the formula (I): where Ri is Ra, RaRt > -, Ra-0-Rb or (Rc) (Rd) N-Rb-, where Ra is H, cyano, - (C = 0) N (Rc) (Rd), -C (= NH) (NH2) , C 1-10 alkyl, C 3-8 alkenyl, C 3-8 cycloalkenyl, C 2-5 heterocyclic radical, or phenyl; wherein Rb is C1-8 alkylene, C2-8 alkenylene, C3-8 cycloalkylene, divalent C3-8 heterocyclic radical, or phenylene; and Rc and Rd are each independently H, C-I-B alkyl, C2-8 alkenyl, C3-scycloalkyl or phenyl; R2 is H, methyl, ethyl, NRpRq, - (CO) NRpRq, - (CO) ORr, -CH2NRpRq, or CH2OR; wherein R p, R q, and R r are independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl; (C3-6 cycloalkyl) (Ci-2 alkylene), benzyl or phenethyl; or Rp and Rq taken together with the nitrogen to which they are attached, form a 4- to 7-membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N; R3 is H, methyl, ethyl, NRsRt, - (CO) NRsRt, - (CO) ORU1 -CH2NRsRt > or CH2ORu; wherein RS) Rt) and Ru are independently selected from C 1-6 alkyl, C3-e.phenyl cycloalkyl; (C3.6 cycloalkyl) (Ci-2 alkylene), benzyl or phenethyl; or Rs and Rt taken together with the nitrogen to which they are attached, form a 4- to 7-membered heterocyclic ring with 0 or 1 heteroatoms selected from O, S, and N; Rs- is methyl, ethyl or H; R ^ is methyl, ethyl or H, R7- is methyl, ethyl or H, X4 is NR1 or S; X1 is CR3; R3 is F, Cl, Br, CHO, Rf, RfRg-, Rf-0-Rg-, or (Rh) (R1) N-Rg-, where f is H, Ci-6 alkyl, C2 alkenyl -6, C2-5 heterocyclic radical or phenyl; wherein Rg is C 1-6 alkylene, C 2-6 alkenylene, C 3-6 cycloalkylene, bivalent C 3-6 heterocyclic radical or phenylene; and Rh and Rj are each independently H, C6 alkyl, C2-6 alkenyl, C3.6 cycloalkyl or phenyl; X2 is NRe or O, provided that X2 is NRe where X-i is N; Re is H or C 1 alkyl; X3 is N; Z is = O or = S; each of R 4 and R 6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C-M alkoxy or C- alkyl; R 5 is H, F, Cl, BR, I, (C = O) R 1, OH, nitro, NRjRm, cyano, phenyl, -OCH 2-Ph C 1 alkoxy or C 1 -4 alkyl; R7 is H, F, Cl, Br, I, (C = O) Rm, OH, nitro, NRjRm, cyano, phenyl, -OCH2-Ph, C-w alkoxy or CM alkyl; wherein each of R j, R k, R 1, and R m is independently selected from H, C 6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C 1-6 alkoxy; each of the above hydrocarbyl groups (including alkyl, alkoxy, phenyl, benzyl, cycloalkyl, etc.) or heterocyclics being independently and optionally substituted with 1 to 3 substituents selected from Ci.sub.3 alkyl, halogen, hydroxy, amino and alkoxy of C1-3", where n is 0, 1 or 2, where n is 2, the portion - (CHR5 ') n = 2- is - (CHR5-CHR7'), where CHRs- is between CHR6- and CHR7-, provided that at least one of R ^ R2, R3, R4, R5, R6 and R7 is different from H when Z is O, and provided that, where Z is O, n = 1, and each of R4, R5, R6, Ry, R3 ', Rs- and R & is H, then (a) where X2 is NH, then R1 is (i) not methyl, pyridyl, phenyl or benzyl, and (b) in where X2 is O, then R1 is nonmethyl, and provided that, where Z is O, X2 is NH, n = 1, R1 is methyl, each of R4, R6, R7, R2-, R3, 5S and 6 is H, then R5 is non-methoxy, or a pharmaceutically acceptable salt, ester or amide thereof 2. A compound according to claim 1 on 1 of the following formula: wherein R-i is Ra, RaRt > -, Ra-0-Rb-, or (Rc) (Rd) N-Rb-, wherein Ra is H, C1-10 alkyl, C3-a alkenyl, C3-8 cycloalkyl, C2- heterocyclic radical 5 or phenyl; wherein Rb is Ci-8 alkylene, C3-8 alkenylene, C3-8 cycloalkylene, divalent C3-8 heterocyclic radical or phenylene; and Rc and Ra are each independently H, Ci-8 alkyl, C3-8 alkenyl, C3_8 cycloalkyl, or phenyl; R2 is ortho or meta, and is methyl or H; Xi is CR3; R3 is F, Cl, Br, Rf, RfRg-, Rf-0-Rg, or (Rh) (R1) N-Rg-, wherein Rf is H, Ci-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C2-5 heterocyclic radical or phenyl; wherein Rg is Ci-6 alkylene, C-i-6 alkenylene, C3-6 cycloalkylene, divalent C3.6 heterocycle radical or phenylene; and ¾ and R, are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, or phenyl; X2 is NRe or O, provided that X2 is NRe when X1 is N; Re is H or Ci-6 alkyl; X3 is N; Z is = 0 or = S; each of R 4 and R 6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C 1-4 alkoxy or C 1-4 alkyl; R5 is H, F, Cl, Br, I, (C = 0) R, -, OH, nitro, NRjRk, cyano, -0CH2-Ph, C1-4 alkoxy or Ci-4 alkyl; R7 is H, F, Cl, Br, I, (C = 0) Rm, OH, nitro, NRjRm, cyano, C-i-4 alkoxy, or C- alkyl; wherein each of Rj, RR, RI, Rm is independently selected from H, C1-6 alkyl, hydroxy and C-i-6 alkoxy; and each of the hydrocarbyl or heterocyclic groups being independently and optionally substituted with 1 to 3 substituents selected from C 1-3 alkyl) halogen, hydroxy, amino and Ci-3 alkoxy; provided that at least one of R-i, R2, R3, R, R5, R6 and R7 is different from H when Z is = 0; or a pharmaceutically acceptable salt, ester or amide thereof. 3. A compound according to claim 1, further characterized in that R1 is Ra, RaRb-, Ra-0-Rb-, or (Rc) (Rd) N-Rb-, where Ra is H, C-alkyl -MO, C3-8 alkenyl, C3-8 cycloalkyl, C2-5 heterocyclic radical or phenyl; wherein R is C 1-6 alkylene, C 2-8 alkenylene, and Re and R d are each independently H, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, or phenyl; R2 'is methyl, ethyl or H; R3 > it is methyl, ethyl or H; R5- is methyl, ethyl or H; R6- is methyl, ethyl or H; R7- is methyl, ethyl or H; X1 is CR3; R3 is F, Cl, Br, methyl, ethyl or propyl; X3 is N; Z is = O or = S; each of R 4 and R 6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, d-4 alkoxy or C-M alkyl; R5 is H, F, Cl, BR, I, (C = 0) Rj, OH, nitro, NRjRk, cyano, -OCH2-Ph, C-M alkoxy or C1-4 alkyl; R7 is H, F, Cl, Br, I, (C = 0) Rm, OH, nitro, NR | Rm, cyano, C- or C 1-4 alkyl; wherein each of Rj, Rk, Ri, and Rm is independently selected from H, Ci-6alkyl, hydroxy, phenyl, benzyl, phenethyl, and Ci-6alkoxy; each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with 1 to 3 substituents selected from Ci-3 alkyl, halogen, hydroxy, amino and C 1-3 alkoxy; n is 1; provided that at least one of R-i, R2, R3, R4, R5, 6 and 7 is different from H when Z is O; or a pharmaceutically acceptable salt, ester or amide thereof. 4. A compound according to claim 1, further characterized in that R1 is H, methyl or ethyl; one of R2-, and R3 'is methyl and the other is H, where R1 is H; R2 is otherwise H; is CR3; R3 is H, F, Cl or Br; X2 is NRe or O; Re is H or Ci-β alkyl; Z is = 0 or = S; each of R 4 and R 6 is independently H, OH, C 1 -4 alkyl, C 1-4 alkoxy, cyano or amino; R5 is H, F, Cl, Br, COOH, OH, amino, cyano, C- | alkoxy. 4 or C 1-4 alkyl; and R7 is H, F, Cl, Br, C-4 alkyl, C 1-4 alkoxy, cyano or amino; provided that at least one of R5 and R7 is not H. 5. - A compound according to claim 1, further characterized in that Ri is H, methyl or ethyl; R2 ', and R3' are independently methyl or H; X1 is CR3 or N; R3 is H, F or Cl; X2 is NRe or O, provided that X2 is NRe where X-? is N; Re is H or C 1-6 alkyl; Z is = 0 or = S; each of R4 and R§ is H; R5 is H, F, Cl, Br, methyl, ethyl or propyl; and R7 is H, F, Cl, Br or Ci ^ alkyl; provided that at least one of R5 and R7 is not H. 6. A compound according to claim 1, further characterized in that X2 is N. 7. A compound according to claim 1, further characterized in that X2 is O. 8. - A compound according to claim 1, further characterized in that R- is H, methyl or ethyl. 9. A compound according to claim 8, further characterized in that R is methyl. 10. A compound according to claim 1, further characterized in that R2- is H. 1 1. - A compound according to claim 1, further characterized in that R2- is methyl. 12. A compound according to claim 1, further characterized in that R3 is H or Cl. 13. A compound according to claim 12, further characterized in that R3 is Cl. 14. - A compound according to claim 1, further characterized in that R5 is F, Cl, Br or methyl and R7 is F, Cl or Br. A compound according to claim 1, further characterized by each of R5 and R7 is independently selected from H, F, Cl, Br, and methyl, provided that at least one is 16.- A compound according to claim 1, further characterized in that each of R4 and R6 is independently H, methyl or Cl 17. A compound according to claim 1, further characterized in that R3 is H or Cl; R5 is F, Cl, Br or methyl and R7 is H, F, Cl or Br. 18 - A compound according to claim 17, further characterized in that each of R and R6 is independently H, methyl or Cl. 19. - A compound according to claim 1, further characterized in that Z is = S. 20. A compound according to claim 1, further characterized in that it is selected from (5-chloro-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-fluoro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-methyl-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-difluoro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (7-chloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-dichloro-1 H -indole-2-yl) - (4-methyl-piperazin-1-yl) -methanone; and (3,5-dichloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone. 21. A compound according to claim 1, further characterized in that it is selected from (6-chloro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (1 H-indol-2-yl) - (3-methyl-piperazin-1-yl) -methanone; (7-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-benzofuran-2-yl) - (4-methyl-piperazin-1-yl) -methanone; and (1 H-indol-2-yl) - (4-methyl-p-piperazin-1-yl) -methanethione. 22. A compound according to claim 20, further characterized in that it is selected from (5-chloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-methyl-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-difluoro-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; and (5,7-dichloro-1 H -indol-2-yl) - (4-methylpiperazin-1-yl) -methanone. 23. A compound according to claim 1, further characterized in that it is selected from (4-methyl-piperazin-1-yl) - (5-trifluoromethyl-1 H -indol-2-yl) -methanone; (7-amino-5-methyl-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-amino-7-methyl-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (7-amino-5-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-amino-7-bromo-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-fluoro-7-methyl-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -metanone; (7-fluoro-5-methyl-1 H -indol-2-yl) - (4-methyl-piperaz'm-1-yl) -methanone; (6-bromo-5-hydroxy-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-6-hydroxy-1H-indol-2-yl) - (4-methy1-p yperazin-1-yl) -methanone; (6-bromo-7-hydroxy-1 H -indol-2-yl) - (4-methyl-p-piperazin-1-yl) -methanone; (4-bromo-7-hydroxy-1 H-indol-2-yl) - (4-methyl-p-piperazin-1-yl) -methanone; (6-bromo-7-methyl-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; and (4-bromo-7-methyl-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone. 24. A compound according to claim 1, further characterized in that it is selected from (5,7-dichloro-1H-indoI-2-yl) -piperazin-1-yl-methanone; (5,7-difluoro-1 H -indole-2-yl) -piperazin-1-yl-methanone; (5,7-difluoro-1 H-indol-2-yl) - (3-methyl-piperazin-1-yl) -methanone; (5,6-difluoro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone and (4,6-difluoro-1 H -indol-2-yl) - (4 -methyl-piperazin-1-yl) -metanone. 25. A compound according to claim 1, further characterized in that it is selected from 1- (5-chloro-1H-indole-2-carbonyl) -4-methyl-piperazine-2-carboxylic acid methyl ester; 4- (5-Chloro-1H-indole-2-carbonyl) -1-methyl-piperazine-2-carboxylic acid methyl ester; 4- (5-chloro-1H-indole-2-carbonyl) -1-methyl-piperazine-2-carboxylic acid amide; 1 - (5-chloro-1 H -indole-2-carbonyl) -4-methyl-piperazine-2-carboxylic acid amide; 4- (5-chloro-1 H -indole-2-carbonyl) -1-methyl-piperazine-2-carboxylic acid methyl-amide; 1- (5-Chloro-1H-indole-2-carbonyl) -4-methyl-piperazine-2-carboxylic acid methylamide; 4- (5-chloro-1 H -indole-2-carbonyl) -1-methyl-piperazine-2-carboxylic acid dimethylamide; 1- (5-Chloro-1H-indole-2-carbonyl) -4-methyl-piperazine-2-carboxylic acid dimethylamide; (5-chloro-1H-indol-2-yl) - (3-hydroxymethyl-4-methyl-piperazin-1-yl) -methanone; (5-chloro-1H-indol-2-yl) - (3-methoxymethyl-4-methyl-piperazin-1-yl) -methanone; (5-chloro-1H-indol-2-ii) - (2-methoxymethyl-4-methyl-piperazin-1-yl) -methanone; (5-chloro-1 H -indol-2-yl) - (4-methyl-3-methylaminomethyl-piperazin-1-yl) -methanone; (5-chloro-1 H -indol-2-yl) - (4-methyl-2-methylaminomethyl-piperazin-1-yl) -methanone; (5-chloro-1 H -indol-2-yl) - (3-dimethylaminomethyl-4-methyl-piperazin-1-yl) -methanone; and (5-chloro-1 H-indol-2-yl) - (2-dimethylaminomethyl-4-methyl-piperazin-1-yl) -methanone. 26. - A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 27. - A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier. 28. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier. 29. A pharmaceutical composition according to claim 23, further characterized in that it comprises a compound selected from (5-chloro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-fluoro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-methy1-H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-difluoro-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (7-chloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-dichloro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (3,5-dichloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (6-chloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (1H-indol-2-yl) - (3-methyl-piperazin-1-yl) -methanone; (7-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-benzofuran-2-yl) - (4-methyl-piperazin-1-yl) -methanone; and (1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanethione. 30. - A packaged drug comprising (a) a pharmaceutical composition comprising a compound of claim 1, 2 or 3, and a pharmaceutically acceptable carrier, and (b) instructions for the administration of said composition for the treatment or prevention of a disease or condition mediated by H4. 31. - The use of a compound as claimed in claim 1, for preparing a medicament for treating an H4 mediated condition in a patient. 32. - The use as claimed in claim 31, wherein the compound is a compound of claim 2. 33. The use as claimed in claim 31, wherein the compound is a compound of claim 3. 34. The use as claimed in claim 31, wherein the compound is selected from: (5-chloro-H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-fluoro-1 H-indol-2-yl) - (4-methyl-p-piperazin-1-yl) -methanone; (5-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-methyl-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (SJ-difluoro-I H-indol ^ -i ^ -methyl-piperazin-1-yl) -methanone; (7-chloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5,7-dichloro-1 H -indol-2-yl) - (4-methylpiperazin-1-yl) -methanone; (3,5-dichloro-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (6-chloro-1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (1 H-indol-2-yl) - (3-methyl-piperazin-1-yl) -methanone; (7-bromo-1 H -indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone; (5-bromo-benzofuran-2-yl) - (4-methyl-piperazin-1-yl) -methanone; and (1 H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanethione. 35. - The use as claimed in claim 31 wherein the condition mediated by H4 is inflammatory disorders, asthma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, autoimmune disease, lymphatic disorders , and immunodeficiency disorders. 36. The use as claimed in claim 35, wherein the condition mediated by H4 is an inflammatory disorder or an allergic disorder. 37. The use as claimed in claim 36, wherein the inflammatory disorder is a condition mediated by inflammation selected from: acute inflammation, allergic inflammation and chronic inflammation. 38. - The use of a compound as claimed in claims 1, 21 or 22, for preparing a medicament for treating asthma in a patient. 39. The use of a compound as claimed in claims 1, 21 or 22 for preparing a medicament for treating an allergic disorder in a patient.
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US6803362B2 (en) | 2004-10-12 |
US20050085487A1 (en) | 2005-04-21 |
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JP4544820B2 (en) | 2010-09-15 |
CA2440438A1 (en) | 2002-09-19 |
CA2440438C (en) | 2011-05-03 |
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